Amidation reactions from the direct coupling of metal carboxylate salts with amines

Article abstract of DOI:10.1021/jo402374c

A general method for the synthesis of amides involving the direct coupling of alkali metal carboxylate salts with amines is described. Amidation of a wide variety of carboxylate salts with either free amines or their ammonium hydrochloride salts can be achieved using HBTU as a coupling agent in combination with Huenig's base. The reaction is highly efficient and is generally complete in as little as 1-2 h, giving the products in good to excellent yields. The protocol is valuable for the coupling of carboxylates for which the corresponding carboxylic acids or acyl chlorides are unstable, less conveniently manipulated/isolated, or are not commercially available. For example, the coupling of amines and α-amino acids with lithium 5-bromo-1H-pyrrole-2-carboxylate, whose corresponding acid that is prone to decarboxylation, allowed for the synthesis of 5-bromo-1H-pyrrole-2-carboxamides, which are analogues of the pyrrole-2-aminoimidazole marine alkaloids. The protocol can be combined with other reactions in a sequenced fashion, as exemplified by the synthesis of acetylenic amides, in a one-pot procedure, via the coupling of a lithium carboxylate salt formed initially by the addition of carbon dioxide to a lithiated terminal alkyne.

Full text of DOI:10.1021/jo402374c

Article
pubs.acs.org/joc
Amidation Reactions from the Direct Coupling of Metal Carboxylate
Salts with Amines
Jordan D. Goodreid, Petar A. Duspara, Caroline Bosch, and Robert A. Batey*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON, Canada,
M5S 3H6
S
* Supporting Information
ABSTRACT: A general method for the synthesis of amides
involving the direct coupling of alkali metal carboxylate salts
with amines is described. Amidation of a wide variety of
carboxylate salts with either free amines or their ammonium
hydrochloride salts can be achieved using HBTU as a coupling
agent in combination with Hunig’s base. The reaction is highly
̈
efficient and is generally complete in as little as 1−2 h, giving the products in good to excellent yields. The protocol is valuable for
the coupling of carboxylates for which the corresponding carboxylic acids or acyl chlorides are unstable, less conveniently
manipulated/isolated, or are not commercially available. For example, the coupling of amines and α-amino acids with lithium 5-
bromo-1H-pyrrole-2-carboxylate, whose corresponding acid that is prone to decarboxylation, allowed for the synthesis of 5-
bromo-1H-pyrrole-2-carboxamides, which are analogues of the pyrrole-2-aminoimidazole marine alkaloids. The protocol can be
combined with other reactions in a sequenced fashion, as exemplified by the synthesis of acetylenic amides, in a one-pot
procedure, via the coupling of a lithium carboxylate salt formed initially by the addition of carbon dioxide to a lithiated terminal
alkyne.
with PPTS (3 equiv)/tertiary amine (2 equiv of Hunig’s base or
INTRODUCTION
̈
■
N-methylmorpholine) additives.10 Although effective, neither
method is appropriate when the corresponding acyl chloride is
unstable or the system is acid-sensitive. Herein, we report the
first general method for the direct coupling of metal carboxylate
salts with amines or amine hydrochloride salts. The newly
developed protocol enables amidations using metal carboxylate
salts for which the corresponding acids or acyl chlorides may be
unstable or inconvenient to manipulate or isolate. Application
of the method for the formation of acetylenic carboxamides,
through a one-pot protocol involving an initial reaction of an
acetylide anion with carbon dioxide, demonstrates its potential
for multistep one-pot amidation reactions from metalated
intermediates.11
Carboxylic amides constitute one of the most important and
ubiquitous of organic functional groups, occurring in natural
products, both peptidic and nonpeptidic, pharmaceuticals,
agrochemicals, materials, and polymers. The privileged nature
of the amide functional group is apparent, for example, from its
occurrence in an estimated 25% of available drugs.1 Most amide
bond formations utilize the reaction of amines in the presence
of acylating agents, such as acyl chlorides,2 or the reaction of
carboxylic acids with amines in the presence of coupling
agents.3 The importance of amides has ensured continued
advances in protocols and reagents based upon these
approaches,4 as well as the development of alternative methods
for amide bond formation.5
In contrast to the use of carboxylic acids, acyl chlorides, and
other activated acylating agents, metal carboxylate salts have
found limited utility for the synthesis of amides. Indeed, the
diminished nucleophilicity of the carboxylate functionality has
enabled carboxylate salts of α-amino acids to be used as a
protected carboxylic acid functionality in peptide couplings.6
For example, alkaline earth metal carboxylate salts of α-amino
acids have been used in reactions with Boc-protected α-amino
acid activated esters (N-hydroxysuccinimidyl or p-nitrophenyl
esters).7 Similar approaches using tetraalkylammonium carbox-
ylate salts for peptide couplings have also been reported.8
Carboxylate salts have also been employed for the synthesis of
amides via in situ acid chloride formation.9 Finally, couplings of
methyl red sodium carboxylate and other alkali metal dye
carboxylates with amines using N,N-diisopropylcarbodiimide
(DIC)/N-hydroxybenzotriazole (HOBt) have been achieved
RESULTS AND DISCUSSION
■
As part of our recent total synthesis of the marine alkaloid
agelastatin A, a method for the formation of a bromopyrrole
amide was required, which culminated in the development of a
direct reaction between diammonium hydrochloride salt 1 with
lithium bromopyrrole carboxylate salt 2, in the presence of the
uronium coupling reagent TPTU (2-(2-pyridon-1-yl)-1,1,3,3-
tetramethyluronium tetrafluoroborate), to give amide 3 with
good regioselectivity in 54% yield (Scheme 1).12 Encouraged
by the success of this preliminary study, we became interested
in whether a general protocol for the direct coupling of alkali
metal carboxylate salts could be developed. A method that
Received: October 24, 2013
© XXXX American Chemical Society
A
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Scheme 1. Selective Acylation of Diammonium Hydrochloride 1 with Lithium Bromopyrrole Carboxylate 2 in the Total
Synthesis of ( )-Agelastatin A
Table 1. Optimization Experiments for the Synthesis of Amide 5a Using Lithium Bromopyrrole Carboxylate 2 and Ammonium
Salt 4
a
entry
method
coupling reagent
iPr2NEt (equiv)
4:5a:6:7:8
1
2
A
A
A
A
B
B
B
B
B
HBTU
1.1
2.1
2.1
1.1
1.1
1.1
2.1
2.1
1.1
45:40:5:10:0
40:10:−:30:20
20:55:0:15:10
20:35:0:25:20
0:100:0:0:0
EDC·HCl
EDC·HCl
PyBOP
b
3
4
5
6
7
HBTU
TPTU
20:60:15:5:5
50:15:−:30:5
15:75:0:10:0
25:65:0:10:0
EDC·HCl
EDC·HCl
PyBOP
b
8
9
a
Ratios determined by 1H NMR analysis of the crude reaction mixtures and are reported to the nearest 5%. Ratios of compounds 4, 5a, and 8 were
b
measured by integration of the Hα signals, whereas 6 and 7 were measured by integration of the H-4 and H-3 pyrrole signals, respectively. 1.0 equiv
of HOBt was added to the reaction. HBTU = 1-[(dimethylamino)(dimethyliminio)methyl]-1H-benzo[d][1,2,3]triazole 3-oxide hexafluorophos-
phate, EDC·HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, PyBOP = (benzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate.
utilizes such salts would be advantageous for a number of
reasons. First, metal carboxylate salts can serve as bench-stable
surrogates to free acids or acid chlorides that are unstable
(prone to decarboxylation/decomposition pathways). For
example, both the free acid and the acid chloride species of
bromopyrrole 2 are reported to be unstable,13−15 whereas the
corresponding lithium carboxylate salt provides access to a
bench-stable alternative that is stable for months.15 Second,
some carboxylic acids are more conveniently manipulated as
the corresponding carboxylate salts, or the carboxylate salts are
more readily available as precursors. Finally, direct (in situ)
activation of a metal carboxylate salt using an appropriate
coupling reagent will often be more time- and cost-effective
than methods utilizing preformed activated esters (e.g., N-
hydroxysuccinimidyl or pentafluorophenyl esters), which
require additional steps to synthesize.
4- and 5-monobromo and 4,5-dibromopyrrole-2-carboxa-
mides are present in a large family of structurally complex and
bioactive pyrrole-2-aminoimidazole (P2AI) marine alkaloids,16
but the corresponding pyrrole-2-carboxylic acids have poor
stability profiles, limiting their application in some syntheses.
Lithium 5-bromo-1H-pyrrole-2-carboxylate 2 was thus chosen
for the initial optimization study. Coupling of 2 with L-
phenylalanine tert-butylester hydrochloride 4 was employed as
a model reaction for optimization studies, using aminium
(HBTU), uronium (TPTU), phosphonium (PyBOP), and
carbodiimide (EDC·HCl) coupling reagents (Table 1). Proton
NMR analysis of the crude reaction mixtures after 1 h revealed
that premixing of the starting materials and coupling reagent(s)
prior to the addition of Hunig’s base (Method A) resulted in
̈
poor conversion to the desired amide 5a. In addition to
significant amounts of remaining amine 4, anhydride 7 and urea
8 were also formed as side-products (Table 1, entries 1−4).17
B
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Scheme 2. Control Experiments for Urea Formation
Table 2. One-Pot Synthesis of Amides 5a−5f Using Lithium Bromopyrrole Carboxylate 2 and Various α-Amino Ester
a
Hydrochloride Salts (Method B)
a
Isolated yields after column chromatographic purification.
Formation of anhydride 7 presumably proceeds through the
homocoupling of carboxylate 2 via an activated ester
species.18,19 Control experiments carried out under similar
conditions demonstrate that urea 8 did not result through the
reaction of excess ammonium salt 4 with EDC·HCl in the
Further optimization revealed that activation of 2 with the
coupling reagent prior to the addition of ammonium salt 4 and
Hunig’s base (Method B) was essential in obtaining a higher
̈
conversion to amide 5a (Table 1, entries 5−9). The order of
addition was found to greatly suppress the formation of
anhydride 7 and resulted in improved yields of amide 5a. Use
of this method, with HBTU as a coupling reagent, resulted in
full conversion to 5a while avoiding the formation of anhydride
7 entirely (Table 1, entry 5). HBTU was thus chosen as the
standard reagent for all further amidation reactions. This result
presence of Hunig’s base, but did form through the analogous
̈
1
reaction with HBTU (27% conversion by H NMR) (Scheme
2, Eq 1). Formation of urea 8 could instead occur from in situ
decarboxylation of 2 and subsequent reaction with 4 using
PyBOP or EDC·HCl. Support for this hypothesis is provided
by the formation of 8 in the reaction of ammonium salt 4,
1
was confirmed in an analogous H NMR experiment utilizing
DMF-d7 as solvent. After 45 min, the reaction between 2 and
HBTU showed full conversion to activated ester 6a (with no
detectable amounts of anhydride 7), which subsequently was
Hunig’s base, and PyBOP in the presence of carbon dioxide gas
̈
1
(57% conversion by H NMR) (Scheme 2, Eq 2). Finally, in
order to test the stability of the pyrrole amide, 5a was
resubjected to the reaction conditions using L-alanine ethyl
ester hydrochloride 9; however, only the formation of urea 1020
was observed (20% conversion by 1H NMR) without
appreciable 5a decomposition or unsymmetrical urea formation
(Scheme 2, Eq 3).
reacted with ammonium salt 4 and Hunig’s base to give 5a as
the sole product.
Application of this improved procedure (Method B) led to
the formation of various primary (5a−5d) and secondary
(5e,5f) amides in excellent isolated yields via the one-pot
coupling of lithium carboxylate 2 with α-amino ester
̈
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a b
,
Table 3. Base-Free Synthesis of Amides 5g−5k Using Lithium Bromopyrrole Carboxylate 2 and Various Amines (Method B)
a
b
Isolated yields after column chromatographic purification. 1.5 equiv of amine was used.
a
Table 4. Base-Free Synthesis of Amides 14a,14b Using Lithium Carboxylate Salts 12a,12b and Amine 13 (Method A)
b
c
entry
carboxylate
temp (°C)
time (h)
amide
yield (%)
dr (L,L:D,L)
1
2
3
4
12a
12a
12b
12b
rt
1
33
1
14a
14a
14b
14b
quant
quant
97
97:3
99:1
95:5
97:3
0−10
rt
0−10
33
96
a
Free base 13 was obtained by treatment of H-Val-OBn·HCl with saturated Na2CO3 (aq) and extraction into CH2Cl2, followed by drying over
b
c
MgSO4 and concentration in vacuo. Isolated yields after column chromatographic purification. Diastereomeric ratio determined by reversed-phase
1
HPLC (C-18 column) of the purified product. These ratios were found to be consistent with those measured initially by H NMR of the crude
reaction mixtures (i.e., diastereomeric enrichment was not observed upon purification).23
ammonium hydrochloride salts (Table 2). Reaction workup
involves simply concentrating the reaction mixture with an air
stream to yield a crude residue that is purified directly by
column chromatography. This operationally simple workup
procedure is less wasteful since it does not require extraction
prior to chromatography, and also could possibly enable the use
of semiautomated techniques. In an effort to expand the
reaction scope, lithium carboxylate 2 was also coupled to a
series of medicinally relevant free amines, giving primary (5g)
and secondary (5h−5k) amides in good yields (Table 3). In
contrast to the examples using amine hydrochloride salts
employs an EDC/HOBt mediated coupling requiring pro-
longed reaction times at low temperature (24 h, 0−5 °C).21a
Performing the same reactions at lower temperatures for
prolonged reaction times gave comparable yields of 14a,14b to
those obtained at room temperature with reduced loss of
stereochemical integrity about the phenylglycine residue (Table
4, entries 2 and 4).
The reaction scope was further evaluated using a variety of
alkali metal salts 15a−15m in couplings with ammonium salt 4,
giving the product amides 16a−16m in good to excellent
isolated yields (Table 5). In contrast to the examples using
lithium carboxylate 2, preactivation of the metal carboxylate
was not necessary in these cases and generally had a negligible
effect on the reaction outcome for the majority of the
substrates; hence, Method A was employed for convenience.
N-Formylation of 4 using 1.0 equiv of sodium formate 15a
resulted in a low yield of 16a (Table 5, entry 1), and a gaseous
byproduct (presumably carbon monoxide) was observed upon
addition of coupling reagent. The use of 2.0 equiv of HBTU
and 15a led to a modest improvement in the yield of 16a
(Table 5, entry 2). Amidation of 4 with ethyl potassium
malonate 15b gave amide 16b in quantitative yield (Table 5,
entry 3), with 15b serving as both a less toxic and cost-effective
substitute to the use of ethyl malonyl chloride. Coupling of
(Table 2), the addition of Hunig’s base was not necessary in the
̈
reactions using free amines.
To test whether this base-free approach could be applied to
more sensitive amide couplings that have been shown to suffer
from epimerization,21 the lithium carboxylate salts of Boc- and
Cbz-L-phenylglycine (12a,12b) were prepared as model
substrates and coupled with the sterically encumbered amine
L-valine benzyl ester 13 (Table 4). Formation of amides
14a,14b proceeded smoothly in 1 h at room temperature in
excellent yields with minimal epimerization of the phenyl-
glycine residue (Table 4, entries 1 and 3).22 For amide 14b, the
observed level of epimerization (5%) at room temperature
(Table 4, entry 3) is comparable to a related protocol that
D
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a b
,
Table 5. Synthesis of Amides 16a−16m Using Metal Carboxylates 15a−15m and Ammonium Salt 4 (Method A)
a
b
Isolated yields after column chromatographic purification. 2.0 equiv of carboxylate salt and HBTU were used.
ketal-protected lithium carboxylate 15c resulted in a 90% yield
of amide 16c (Table 5, entry 4). Carboxylate 15c, which is
bench-stable for several months, was prepared in 89% yield by
hydrolysis of the corresponding ethyl ester derivative with 1.0
equiv of LiOH·H2O via a modified literature procedure.24
Attempts to couple the corresponding unprotected keto
derivative of 15c proved unsuccessful, yielding only urea 8 in
54% yield. The ability of the unprotected keto acid derivative of
15c to undergo decarboxylation under these conditions is
necessary in order for urea 8 to form, just as was observed for
reaction of 2, which can similarly decarboxylate, leading to the
formation of 8 (Table 1 and Scheme 2). Reaction of
unprotected lithium L-lactate 15e gave amide 16e in 85%
yield via Method A (Table 5, entry 6), whereas Method B was
unsuccessful. Penicillin G potassium carboxylate 15f, which is
only sold commercially as the carboxylate salt for stability
reasons, was coupled smoothly to give amide 16f in 80% yield
(Table 5, entry 7). This example provides further evidence that
late stage amidation reactions of structurally complex
carboxylate salts can be accomplished even in the presence of
highly reactive functionalities, such as β-lactams. Coupling of
1.0 equiv of sodium acrylate 15h proceeded in low yield and
only via Method A (Table 5, entry 9) due to a competing
polymerization pathway. As was the case for the reaction of
sodium formate, increasing the number of equivalents of 15h
and HBTU had a minimal effect on the outcome of the reaction
(Table 5, entry 10). Conversely, coupling reactions of other
unsaturated carboxylate salts, namely, potassium sorbate 15i
E
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ab c
, ,
Table 6. One-Pot Synthesis of Acetylenic Amides 18a−18f from Terminal Alkynes 17a−17f (Method C)
a
b
c
n
Isolated yields after column chromatographic purification. Alkyne 17e (1.0 equiv), BuLi (1.0 equiv), and 4 (1.0 equiv) were used. Alkyne 17f
n
(1.6 equiv), BuLi (1.0 equiv), and 4 (1.6 equiv) were used.
and sodium methacrylate 15j, proceeded smoothly and in
excellent yields (Table 5, entries 11 and 12). Coupling of aryl
carboxylate salts 15k−15m also occurred in excellent yields
(Table 5, entries 13−15) even for electron-deficient nicotinic
and picolinic acid derivatives 15l and 15m, respectively.
A more general synthetic approach to acetylenic amides
utilizing trapping of metalated acetylides with carbon dioxide to
generate carboxylate salt intermediates, followed by in situ
coupling with amines, would, therefore, be of considerable
interest. Accordingly, a variety of terminal alkynes 17a−17f
were lithiated using nBuLi and then reacted with carbon dioxide
to give the intermediate lithium carboxylate salts, which could
then be directly coupled with amine 4 in their crude state to
give amides 18a−18f (Table 6). Good overall yields of the
acetylenic amides could be obtained using a slight excess of 4,
17, and HBTU (1.3 equiv). The carboxylate salt derived from
phenylacetylene 17e on the other hand was coupled in 84%
overall yield using only a stoichiometric amount of reagents
(Table 6, entry 5). Using the standard conditions (1.3 equiv of
reagents), the carboxylate salt derived from 3-ethynylpyridine
17f was only coupled in modest yield; however, a quantitative
isolated yield was obtained by employing additional reagent
equivalents (Table 6, entries 6 and 7).
Since there are many reactions that form carboxylate salts in
situ, it was also of interest to evaluate whether sequenced or
domino transformations could be combined with the newly
developed amidation protocol. To evaluate the feasibility of
such a strategy, the reaction of in situ generated acetylenic
carboxylate salts for the formation of acetylenic amides was
chosen as a model study. Acetylenic amides serve as useful
building blocks in the synthesis of heterocycles as well as other
functionalities.25 Amidations using free acetylenic acids, such as
propiolic acid or but-2-ynoic acid, with peptide coupling
reagents provide one classical approach to their synthesis. For
example, isolated 3-(triisopropylsilyl)propiolic acid (synthe-
sized via the corresponding acetylide addition to carbon
dioxide) was used in a PyBOP mediated coupling with DL-
serine methyl ester hydrochloride.26 An alternative approach to
their synthesis utilizes low-temperature trapping of a lithiated
acetylide with phenyl isocyanate or a magnesium acetylide with
Me3SiNCO.27 Although these methods have proven useful,
their application can be limited by the lack of access to
appropriate starting materials or low product yields.
In summary, this study represents the first general
investigation into the direct use of metal carboxylate salts in
amidation reactions with amines. The full scope of this reaction
was explored through the coupling of a wide variety of alkali
metal carboxylate salts with various amine or ammonium
hydrochloride salts using HBTU as a coupling reagent. The
amide products were obtained in good to excellent yields, using
F
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112.6, 104.8, 83.1, 56.0, 38.8, 28.3; HRMS (ESI+) m/z calcd for
C18H22BrN2O3 [M + H]+: 393.0808, found 393.0813.
one of two reaction protocols depending upon the carboxylate
salt used. The first protocol involves the direct reaction of all of
the reagents, while the second protocol employs the initial
reaction of the carboxylate salt and coupling reagent, followed
by subsequent addition of the amine or hydrochloride salt.
Extension of the method to a three-step one-pot synthesis of
acetylenic amides was possible using an approach in which
acetylenic carboxylates were synthesized from terminal alkynes,
nBuLi, and carbon dioxide. Further application of this reaction
can be envisaged for related amide formations, including
multistep variants and cyclization reactions of carboxylate salts.
(S)-Methyl-2-(5-bromo-1H-pyrrole-2-carboxamido)-4-methyl-
pentanoate (5b). Yellow crystalline solid (81.5 mg, 99%); mp 92−93
°C (CH2Cl2); Rf 0.25 (4:1 hexanes:EtOAc); [α]2D5 −15.4 (c 1.04,
MeOH); IR (thin film in CH2Cl2) νmax 3312 (br), 3181 (br), 2957,
1728, 1634, 1558, 1526, 1439, 1207 cm−1; 1H NMR (500 MHz,
CDCl3) δ 10.40 (1H, br s), 6.57 (1H, dd, J = 4.0, 2.5 Hz), 6.42 (1H, br
d, J = 8.5 Hz), 6.15 (1H, dd, J = 4.0, 2.5 Hz), 4.88 (1H, ddd, J = 8.5,
8.5, 5.0 Hz), 3.75 (3H, s), 1.77−1.59 (3H, m), 0.97 (3H, d, J = 6.5
Hz), 0.95 (3H, d, J = 6.5 Hz); 13C NMR (125 MHz, CDCl3) δ 174.0,
160.0, 126.7, 112.0, 111.3, 104.3, 52.6, 50.7, 41.9, 25.1, 23.0, 22.1;
HRMS (DART) mass calcd for C12H18BrN2O3 [M + H]: 317.0501,
found 317.0494.
EXPERIMENTAL SECTION
(S)-Methyl-2-(5-bromo-1H-pyrrole-2-carboxamido)-3-(1H-indol-
3-yl)propanoate (5c). Beige solid (103.2 mg, 93%); mp 77−78 °C
(CH2Cl2); Rf 0.22 (2:1 hexanes:EtOAc); [α]2D6 +49.5 (c 0.56, CHCl3);
IR (thin film in CH2Cl2) νmax 3416 (br), 2953, 2926, 1728, 1624,
■
All reactions were performed under nitrogen in flame-dried glassware.
Tetrahydrofuran was freshly distilled from sodium/benzophenone
ketyl under nitrogen. Dichloromethane was freshly distilled from
calcium hydride under nitrogen. Anhydrous dimethylformamide was
obtained as ≥99.9% pure and stored under argon. Flash chromatog-
raphy on silica gel (60 Å, 230−400 mesh) was performed with reagent
grade solvents. Analytical thin-layer chromatography (TLC) was
performed on precoated silica gel plates and visualized with a UV254
lamp. Solvent ratios for chromatography and Rf values are reported as
v/v ratios. Melting points are uncorrected and obtained on >95% pure
compounds without any further recrystallization. All 1-D (1H, 13C)
NMR spectra were obtained on 300, 400, 500, and 600 MHz
spectrometers as solutions in deuterated solvents. Chemical shifts are
reported in δ parts per million (ppm) values. Proton chemical shifts
were internally referenced to tetramethylsilane (δ 0.00) for CDCl3 or
to the residual proton resonance in CD3OD (δ 3.31) and DMSO-d6 (δ
2.49). Carbon chemical shifts were internally referenced to the solvent
resonances in CDCl3 (δ 77.16 ppm), CD3OD (δ 49.15 ppm), or
DMSO-d6 (δ 39.51 ppm). Peak multiplicities are designated by the
following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad; J, coupling constant in Hz (rounded to the
nearest 0.5 Hz). Exact mass measurements were performed on
quadrupole time-of-flight mass spectrometers utilizing electrospray
ionization (ESI-QTOF) or direct analysis in real-time ionization
(DART-TOF). Both the measured and the calculated m/z values for
ESI-QTOF correspond to the ionic species of interest (are corrected
for the mass of an electron), whereas those for DART correspond to
the mass of the neutral species (not corrected for the mass of an
electron).
1
1558, 1456 cm−1; H NMR (500 MHz, CD3OD; note: the amide,
pyrrole, and indole NH signals were not observed due to deuterium
exchange) δ 7.55−7.51 (1H, m), 7.34−7.30 (1H, m), 7.10−7.06 (2H,
m), 7.02−6.97 (1H, m), 6.72 (1H, d, J = 4.0 Hz), 6.11 (1H, d, J = 4.0
Hz), 4.87 (1H, dd, J = 7.5, 6.0 Hz), 3.67 (3H, s), 3.37 (1H, ddd, J =
14.5, 6.0, 0.5 Hz), 3.27 (1H, ddd, J = 14.5, 7.5, 0.5 Hz); 13C NMR
(125 MHz, CD3OD) δ 174.4, 162.3, 138.2, 128.8, 128.3, 124.5, 122.6,
120.0, 119.3, 114.2, 112.7, 112.5, 111.0, 104.9, 55.0, 52.8, 28.6; HRMS
(DART) mass calcd for C17H17BrN3O3 [M + H]: 390.0453, found
390.0464.
Ethyl-2-(5-bromo-1H-pyrrole-2-carboxamido)acetate (5d). Beige
crystalline solid (50.8 mg, 85%); mp 143−145 °C (CH2Cl2); Rf 0.43
(2:1 hexanes:EtOAc); IR (thin film in CH2Cl2) νmax 3400, 3175 (br),
1
2984, 1730, 1639, 1472, 1393 cm−1; H NMR (400 MHz, CD3OD;
note: the amide and pyrrole NH signals were not observed due to
deuterium exchange) δ 6.76 (1H, d, J = 4.0 Hz), 6.15 (1H, d, J = 4.0
Hz), 4.19 (2H, q, J = 7.5 Hz), 4.04 (2H, s), 1.26 (3H, t, J = 7.5 Hz);
13C NMR (100 MHz, CD3OD) δ 171.8, 163.0, 128.3, 113.8, 112.7,
104.9, 62.4, 42.0, 14.6; HRMS (ESI+) m/z calcd for C9H12BrN2O3 [M
+ H]+: 275.0025, found 275.0034.
(S)-Benzyl-1-(5-bromo-1H-pyrrole-2-carbonyl)pyrrolidine-2-car-
boxylate (5e). White foam (91.6 mg, 94%); Rf 0.37 (2:1
hexanes:EtOAc); [α]2D6 −54.5 (c 0.89, MeOH); IR (thin film in
CH2Cl2) νmax 3182 (br), 3070, 3033, 2958, 2879, 1744, 1592, 1448,
1386, 1169 cm−1; 1H NMR (400 MHz, CD3OD; note: the pyrrole NH
signal was not observed due to deuterium exchange) δ 7.42−7.22 (5H,
m), 6.69 (1H, d, J = 3.0 Hz), 6.20 (1H, d, J = 3.0 Hz), 5.16 (2H, s),
4.64 (1H, dd, J = 7.5, 4.5 Hz), 3.94−3.78 (2H, m), 2.34−2.21 (1H,
m), 2.14−1.90 (3H, m); 13C NMR (100 MHz, CD3OD) δ 173.9,
161.8, 137.5, 129.7, 129.4, 129.2, 128.1, 116.3, 113.0, 105.5, 68.0, 61.8,
50.1, 29.8, 26.4; HRMS (DART) mass calcd for C17H18BrN2O3 [M +
H]: 377.0501, found 377.0503.
(2S,4R)-Methyl-1-(5-bromo-1H-pyrrole-2-carbonyl)-4-hydroxy-
pyrrolidine-2-carboxylate (5f). Light yellow solid (76.6 mg, 88%);
decomposition temp 170 °C; Rf 0.41 (EtOAc); [α]2D3 −58.5 (c 0.76,
MeOH); IR (solid) νmax 3416, 3130, 2957, 2925, 1732, 1616, 1431,
1215, 1184 cm−1; 1H NMR (400 MHz, CD3OD; note: the pyrrole NH
and alcohol OH signals were not observed due to deuterium
exchange) δ 6.67 (1H, d, J = 4.0 Hz), 6.21 (1H, d, J = 4.0 Hz),
4.71 (1H, dd, J = 9.0, 9.0 Hz), 4.53 (1H, br s), 3.98 (1H, dd, J = 11.0,
4.0 Hz), 3.82 (1H, d, J = 11.0 Hz), 3.73 (3H, s), 2.34−2.23 (1H, m),
2.05 (1H, ddd, J = 13.0, 9.0, 4.0 Hz); 13C NMR (100 MHz, CD3OD)
δ 174.7, 162.4, 127.9, 116.4, 112.9, 105.5, 71.5, 60.3, 58.3, 52.9, 38.1;
HRMS (DART) mass calcd for C11H14BrN2O4 [M + H]: 317.0137,
found 317.0140.
Amides Synthesized via General Procedure B. Representative
Procedure: (S)-tert-Butyl-2-(5-bromo-1H-pyrrole-2-carboxamido)-3-
phenylpropanoate (5a). In a flame-dried vial with a stir bar were
loaded lithium 5-bromo-1H-pyrrole-2-carboxylate 2 (14.8 mg, 0.075
mmol, 1.0 equiv) and DMF (1 mL). To the resulting solution was
added HBTU (31.8 mg, 0.084 mmol, 1.1 equiv), and the mixture was
stirred for 1 h at room temperature. A second vial was prepared with L-
phenylalanine tert-butyl ester hydrochloride 4 (19.6 mg, 0.076 mmol,
1.0 equiv) and it was slurried in DMF (1 mL) before dropwise
addition of Hunig’s base (15 μL, 0.086 mmol, 1.1 equiv). This solution
̈
was then cannula transferred to the carboxylate/HBTU mixture, and
the reaction mixture was stirred for an additional 1 h at room
temperature. The crude reaction mixture was then concentrated down
to a thick residue using an air stream before being loaded directly onto
a silica column. Flash chromatography (3:1 hexanes:EtOAc) of the
crude residue afforded 5a (27.9 mg, 93% yield) as a light yellow
crystalline solid; mp 50−51 °C (CH2Cl2); Rf 0.61 (3:1 hexanes:E-
tOAc); [α]2D3 +73.2 (c 0.83, CHCl3); IR (thin film in CH2Cl2) νmax
3287 (br), 3196 (br), 2976, 2961, 2926, 2855, 1717, 1626, 1456, 1367,
1153 cm−1; 1H NMR (400 MHz, CD3OD; note: the amide and
pyrrole NH signals were not observed due to deuterium exchange) δ
7.30−7.17 (5H, m), 6.76 (1H, d, J = 4.0 Hz), 6.12 (1H, d, J = 4.0 Hz),
4.68 (1H, dd, J = 8.5, 6.5 Hz), 3.16 (1H, dd, J = 14.0, 6.5 Hz), 3.06
(1H, dd, J = 14.0, 8.5 Hz), 1.40 (9H, s); 13C NMR (100 MHz,
CD3OD) δ 172.7, 162.3, 138.6, 130.5, 129.6, 128.3, 127.9, 114.1,
5-Bromo-N-phenethyl-1H-pyrrole-2-carboxamide (5g). White
solid (63.2 mg, 85%); mp 134−135 °C (CH2Cl2); Rf 0.50 (2:1
hexanes:EtOAc); IR (solid) νmax 3363 (br), 3219 (br), 3026, 2924,
2849, 1615, 1599, 1551, 1453, 1395 cm−1; 1H NMR (300 MHz,
CD3OD; note: the amide and pyrrole NH signals were not observed
due to deuterium exchange) δ 7.31−7.14 (5H, m), 6.67 (1H, d, J = 4.0
Hz), 6.11 (1H, d, J = 4.0 Hz), 3.55−3.47 (2H, m), 2.90−2.82 (2H,
G
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m); 13C NMR (75 MHz, CD3OD) δ 162.7, 140.8, 130.0, 129.6, 128.9,
127.5, 113.2, 112.5, 104.3, 42.2, 37.0; HRMS (ESI+) m/z calcd for
C13H14BrN2O [M + H]+: 293.0284, found 293.0294.
110.1, 107.8; HRMS (ESI+) m/z calcd for C10H8BrN2O3 [M + H]+:
282.9713, found 282.9712.
5-Bromo-1H-pyrrole-2-carboxylic anhydride (7). Synthesized via
the same procedure as for compound 6a except 2.3 equiv of lithium 5-
bromo-1H-pyrrole-2-carboxylate 2 was used. Light orange solid (18.8
mg, 16%); mp 84−86 °C (CH2Cl2); Rf 0.07 (2:1 hexanes:EtOAc); IR
(solid) νmax 3184, 2923, 1643, 1430, 1378, 1187, 1031 cm−1; 1H NMR
(400 MHz, CD3OD; note: the pyrrole NH signal was not observed
due to deuterium exchange) δ 6.79 (2H, d, J = 4.0 Hz), 6.15 (2H, d, J
= 4.0 Hz); 13C NMR (100 MHz, CD3OD) δ 163.4, 125.9, 118.0,
113.1, 106.0; HRMS (ESI−) m/z calcd for C10H5Br2N2O3 [M − H]−:
358.8672, found 358.8672.
(5-Bromo-1H-pyrrol-2-yl)(pyrrolidin-1-yl)methanone (5h). White
solid (49.0 mg, 77%); sublimation temp 190 °C; Rf 0.20 (2:1
hexanes:EtOAc); IR (solid) νmax 3137, 2969, 1582, 1445, 1386, 831
cm−1; 1H NMR (500 MHz, (CD3)2SO) δ 12.15 (1H, br s), 6.56 (1H,
dd, J = 3.5, 2.5 Hz), 6.16 (1H, dd, J = 3.5, 2.5 Hz), 3.70−3.55 (2H, m),
3.53−3.38 (2H, m), 2.00−1.70 (4H, m); 13C NMR (125 MHz,
(CD3)2SO) δ 158.9, 127.8, 113.4, 111.0, 102.6, 47.6, 46.6, 26.2, 23.4;
HRMS (DART) mass calcd for C9H12BrN2O [M + H]: 243.0133,
found 243.0137.
(5-Bromo-1H-pyrrol-2-yl)(morpholino)methanone (5i). White
solid (49.7 mg, 87%); mp 170−172 °C (CHCl3); Rf 0.18 (2:1
hexanes:EtOAc); IR (solid) νmax 3192 (br), 2961, 2917, 2850, 1583,
(2S,2′S)-di-tert-Butyl 2,2′-(carbonylbis(azanediyl))bis(3-phenyl-
propanoate) (8). In a flame-dried 25 mL flask with a stir bar was
loaded L-phenylalanine tert-butyl ester hydrochloride 4 (203.2 mg,
0.788 mmol, 1.8 equiv) and it was slurried in CH2Cl2 (5 mL) before
1
1465, 1430, 1114, 966, 813 cm−1; H NMR (300 MHz, CDCl3) δ
dropwise addition of Hunig’s base (140 μL, 0.804 mmol, 1.9 equiv),
̈
10.62 (1H, br s), 6.42 (1H, dd, J = 3.5, 2.5 Hz), 6.17 (1H, dd, J = 3.5,
2.5 Hz), 3.92−3.81 (4H, m), 3.79−3.70 (4H, m); 13C NMR (75 MHz,
CDCl3) δ 161.1, 125.8, 114.0, 111.7, 103.8, 67.0, 45.5; HRMS
(DART) mass calcd for C9H12BrN2O2 [M + H]: 259.0082, found
259.0088.
(5-Bromo-1H-pyrrol-2-yl)(4-phenylpiperazin-1-yl)methanone
(5j). White solid (71.6 mg, 80%); mp 196−197 °C (CHCl3); Rf 0.68
(2:1 hexanes:EtOAc); IR (solid) νmax 3132, 3086, 2966, 2857, 1597,
1465, 1442, 1387, 1370, 1289, 1224, 1203, 1027 cm−1; 1H NMR (500
MHz, (CD3)2SO) δ 12.22 (1H, br s), 7.26−7.19 (2H, m), 6.97−6.92
(2H, m), 6.83−6.77 (1H, m), 6.50 (1H, d, J = 3.5 Hz), 6.17 (1H, d, J =
3.5 Hz), 3.83−3.72 (4H, m), 3.20−3.13 (4H, m); 13C NMR (125
MHz, (CD3)2SO) δ 160.5, 150.7, 129.0, 126.1, 119.2, 115.7, 113.4,
110.5, 102.2, 48.5, 44.2; HRMS (ESI+) m/z calcd for C15H17BrN3O
[M + H]+: 334.0549, found 334.0534.
followed by addition of 1,1′-carbonyldiimidazole (70.0 mg, 0.432
mmol, 1.0 equiv). The reaction mixture was stirred for 12 h at room
temperature before being concentrated in vacuo to give a crude
residue. Flash chromatography (3:1 hexanes:EtOAc) of the crude
residue afforded 8 (160.5 mg, 79% yield) as a white solid; mp 136−
137 °C (CH2Cl2); Rf 0.49 (3:1 hexanes:EtOAc); [α]2D3 +70.3 (c 1.06,
CHCl3); IR (solid) νmax 3303 (br), 2977, 1730, 1623, 1563, 1364,
1445, 1104 cm−1; 1H NMR (400 MHz, CD3OD; note: the amide NH
signal was not observed due to deuterium exchange) δ 7.30−7.24 (4H,
m), 7.23−7.17 (6H, m), 4.45−4.38 (2H, m), 3.00 (2H, dd, J = 14.0,
6.5 Hz), 2.95 (2H, dd, J = 14.0, 7.0 Hz), 1.37 (18H, s); 13C NMR (100
MHz, CD3OD) δ 173.2, 159.6, 138.3, 130.7, 129.5, 127.9, 82.9, 56.3,
39.5, 28.4; HRMS (ESI+) m/z calcd for C27H37N2O5 [M + H]+:
469.2697, found 469.2694.
(5-Bromo-1H-pyrrol-2-yl)(3,4-dihydroisoquinolin-2(1H)-yl)-
methanone (5k). Light yellow solid (70.3 mg, 83%); mp 120−121 °C
(CH2Cl2); Rf 0.56 (2:1 hexanes:EtOAc); IR (thin film in CH2Cl2) νmax
Lithium (S)-2-((tert-butoxycarbonyl)amino)-2-phenylacetate
(12a). In a 150 mL lyophilization flask were loaded Boc-L-
phenylglycine 11a (1.019 g, 4.06 mmol) and 3:2 MeCN/H2O (25
mL). To this solution was added LiOH·H2O (170.5 mg, 4.06 mmol),
and the mixture was stirred vigorously for 10 min (LiOH should be
completely dissolved) before removing the stir bar and cooling the
solution to −78 °C until the mixture became completely solid.
Removal of the solvents by lyophilization overnight afforded 12a
(1.022 g, 98%) as a white solid; decomposition temp 80 °C; [α]D21
+102.8 (c 1.01, MeOH); IR (solid) νmax 2977, 1684, 1601, 1390, 1366,
1
3177 (br), 3078, 3024, 2961, 2934, 2847, 1595, 1447, 1387 cm−1; H
NMR (400 MHz, (CD3)2SO) δ 12.23 (1H, br s), 7.25−7.14 (4H, m),
6.60 (1H, d, J = 4.0 Hz), 6.20 (1H, d, J = 4.0 Hz), 4.79 (2H, s), 3.85
(2H, t, J = 6.0 Hz), 2.88 (2H, t, J = 6.0 Hz); 13C NMR (100 MHz,
(CD3)2SO) δ 160.7, 134.8, 133.4, 128.4, 126.5, 126.35, 126.33, 126.2,
113.4, 110.6, 102.2, 46.3, 42.7, 28.4; HRMS (DART) mass calcd for
C14H14BrN2O [M + H]: 305.0289, found 305.0276.
1
1165 cm−1; H NMR (400 MHz, CD3OD; note: mixture of rotamers
1H-Benzo[d][1,2,3]triazol-1-yl 5-bromo-1H-pyrrole-2-carboxylate
(6a). In a flame-dried vial with a stir bar were loaded lithium 5-bromo-
1H-pyrrole-2-carboxylate 2 (65.4 mg, 0.334 mmol, 1.0 equiv) and
DMF (2 mL). HBTU (130.0 mg, 0.343 mmol, 1.0 equiv) was added,
and the mixture was stirred for 1 h at room temperature. The crude
reaction mixture was then concentrated down to a thick residue using
an air stream before being loaded directly onto a silica column. Flash
chromatography (4:1 hexanes:EtOAc) of the crude residue afforded 6a
(79.5 mg, 78% yield) as a light orange solid; mp 161−163 °C
(CH2Cl2); Rf 0.35 (4:1 hexanes:EtOAc); IR (solid) νmax 3050, 2955,
and the carbamate NH signal was not observed due to deuterium
exchange) δ 7.42 (2H, d, J = 7.5 Hz), 7.27 (2H, t, J = 7.5 Hz), 7.20
(1H, t, J = 7.5 Hz), 5.00−4.78 (1H, m), 1.50−1.20 (9H, m); 13C NMR
(100 MHz, CD3OD; note: mixture of rotamers) δ 177.2, 157.1, 142.5,
129.3, 128.23, 128.14, 81.2, 80.4, 62.7, 61.6, 28.9, 28.6; HRMS (ESI−)
m/z calcd for C13H16NO4 [M − Li]−: 250.1085, found 250.1088.
Lithium (S)-2-(((benzyloxy)carbonyl)amino)-2-phenylacetate
(12b). Synthesized via the same procedure as for compound 12a
except a 7:4 MeCN/H2O solvent system was used for Cbz-L-
phenylglycine 11b. White solid; decomposition temp 240 °C; [α]D21
+108.8 (c 1.14, DMSO); IR (solid) νmax 3420, 3064, 3034, 2966, 1702,
1601, 1405, 1388, 1350, 1058 cm−1; 1H NMR (300 MHz, (CD3)2SO)
δ 7.40−7.09 (10H, m), 6.99 (1H, d, J = 6.5 Hz), 5.00 (1H, d, J = 12.5
Hz), 4.93 (1H, d, J = 12.5 Hz), 4.60 (1H, d, J = 6.5 Hz); 13C NMR (75
MHz, (CD3)2SO) δ 166.0, 150.6, 138.6, 133.3, 124.4, 123.74, 123.68,
123.4, 122.7, 121.9, 61.1, 56.4; HRMS (ESI−) m/z calcd for
C16H14NO4 [M − Li]−: 284.0928, found 284.0937.
Lithium 2-(2-methyl-1,3-dioxolan-2-yl)acetate (15c). In a 100 mL
Schlenk flask with a stir bar was loaded ethyl 2-(2-methyl-1,3-dioxolan-
2-yl)acetate28 (2.89 g, 17.11 mmol). A 1.05 M (aq) solution of LiOH
(16.3 mL, 17.11 mmol) was then added, and the reaction mixture was
stirred vigorously for 5 h at 50 °C. The solution was then carefully
concentrated under reduced pressure at 50 °C to yield a thick white
residue. Evaporation from toluene (2 × 30 mL) and further drying in
vacuo afforded 15c (2.31 g, 89% yield) as a white solid; decomposition
temp 200 °C; IR (solid) νmax 2905, 1597, 1418, 1201, 1151, 1049
cm−1; 1H NMR (300 MHz, CD3OD) δ 4.01−3.88 (4H, m), 2.49 (2H,
s), 1.47 (3H, s); 13C NMR (100 MHz, CD3OD) δ 178.3, 110.0, 65.6,
1
2232, 1761, 1420, 1366, 1075 cm−1; H NMR (400 MHz, CD3OD;
note: the pyrrole NH signal was not observed due to deuterium
exchange) δ 8.05 (1H, ddd, J = 8.5, 1.0, 1.0 Hz), 7.66−7.60 (2H, m),
7.55−7.48 (1H, m), 7.33 (1H, d, J = 4.0 Hz), 6.43 (1H, d, J = 4.0 Hz);
13C NMR (100 MHz, CD3OD) δ 157.0, 144.7, 130.5, 130.4, 126.6,
122.5, 120.9, 118.9, 115.1, 111.8, 110.1; HRMS (ESI+) m/z calcd for
C11H8BrN4O2 [M + H]+: 306.9825, found 306.9824.
2-Oxopyridin-1(2H)-yl 5-bromo-1H-pyrrole-2-carboxylate (6b).
Synthesized via the same procedure as for compound 6a except
TPTU was used in place of HBTU. Note: product 6b contains a
1,1,3,3-tetramethylurea (TMU) impurity (approximately 5% w/w by
1H NMR). White solid (110.8 mg, 71%); decomposition temp 70 °C;
Rf 0.36 (1:1 hexanes:EtOAc); IR (solid) νmax 3113, 3059, 2953, 1754,
1650, 1577, 1534, 1378, 1152, 1030 cm−1; 1H NMR (400 MHz,
CD3OD; note: the pyrrole NH signal was not observed due to
deuterium exchange) δ 7.85 (1H, dd, J = 7.0, 2.0 Hz), 7.65−7.57 (1H,
m), 7.14 (1H, d, J = 4.0 Hz), 6.73 (1H, dd, J = 9.0, 2.0 Hz), 6.44 (1H,
ddd, J = 7.0, 7.0, 2.0 Hz), 6.33 (1H, d, J = 4.0 Hz); 13C NMR (100
MHz, CD3OD) δ 160.0, 157.1, 142.2, 138.2, 122.7, 121.3, 120.1, 114.4,
H
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48.6, 24.7; HRMS (ESI−) m/z calcd for C6H9O4 [M − Li]−: 145.0506,
found 145.0503.
3.06 (1H, dd, J = 14.0, 6.5 Hz), 2.56 (2H, s), 1.40 (9H, s), 1.35 (3H,
s); 13C NMR (100 MHz, CDCl3) δ 170.9, 168.5, 136.5, 129.6, 128.5,
127.0, 107.9, 82.2, 64.72, 64.69, 53.6, 46.2, 38.3, 28.1, 24.0; HRMS
(DART) mass calcd for C19H28NO5 [M + H]: 350.1962, found
350.1971.
(S)-tert-Butyl-2-(2-oxopropanamido)-3-phenylpropanoate (16d).
Light yellow oil (215.4 mg, 77%); Rf 0.46 (4:1 hexanes:EtOAc); [α]D23
+33.4 (c 1.49, CHCl3); IR (neat) νmax 3397 (br), 3030, 3004, 2979,
2934, 1732, 1684, 1519, 1367, 1356, 1254, 1155 cm−1; 1H NMR (300
MHz, CDCl3) δ 7.38−7.19 (4H, m), 7.18−7.10 (2H, m), 4.68 (1H,
ddd, J = 8.0, 5.5, 5.5 Hz), 3.17−3.03 (2H, m), 2.44 (3H, s), 1.40 (9H,
s); 13C NMR (75 MHz, CDCl3) δ 196.3, 169.7, 159.6, 135.8, 129.5,
128.6, 127.3, 82.9, 53.8, 38.2, 28.0, 24.5; HRMS (DART) mass calcd
for C16H22NO4 [M + H]: 292.1543, found 292.1554.
(S)-tert-Butyl-2-((S)-2-hydroxypropanamido)-3-phenyl-
propanoate (16e).31 White crystalline solid (147.6 mg, 85%); mp
72−73 °C (CH2Cl2); Rf 0.41 (1:1 hexanes:EtOAc); [α]2D3 +44.8 (c
1.11, CHCl3) [lit.31 [α]D20 +36.8 (c 1.0, CHCl3), dr >20:1]; IR (thin
film in CH2Cl2) νmax 3396 (br), 3032, 2979, 2934, 1729, 1651, 1524,
1367, 1155 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.32−7.20 (3H, m),
7.18−7.13 (2H, m), 6.89 (1H, br d, J = 7.5 Hz), 4.75 (1H, ddd, J = 7.5,
6.0, 6.0 Hz), 4.20 (1H, br qd, J = 7.0, 4.5 Hz), 3.13 (1H, dd, J = 14.0,
6.0 Hz), 3.08 (1H, dd, J = 14.0, 6.0 Hz), 2.73 (1H, br d, J = 4.5 Hz),
1.41 (9H, s), 1.35 (3H, d, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ
174.0, 170.7, 136.2, 129.6, 128.5, 127.1, 82.6, 68.5, 53.2, 38.2, 28.1,
21.3; HRMS (DART) mass calcd for C16H24NO4 [M + H]: 294.1700,
found 294.1711.
(S)-tert-Butyl-2-((2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenyl-
acetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxamido)-3-
phenylpropanoate (16f). Light yellow crystalline solid (125.7 mg,
80%); mp 62−63 °C (CH2Cl2); Rf 0.31 (2:1 hexanes:EtOAc); [α]D23
+192.1 (c 1.21, CHCl3); IR (thin film in CH2Cl2) νmax 3303 (br),
3063, 3029, 2977, 2932, 1785, 1730, 1661, 1523, 1454, 1367, 1154
cm−1; 1H NMR (500 MHz, CD3OD; note: the amide NH signals were
not observed due to deuterium exchange) δ 7.33−7.18 (10H, m), 5.56
(1H, d, J = 4.5 Hz), 5.45 (1H, d, J = 4.5 Hz), 4.57 (1H, dd, J = 9.5, 5.5
Hz), 4.13 (1H, s), 3.60 (1H, d, J = 14.5 Hz), 3.56 (1H, d, J = 14.5 Hz),
3.16 (1H, dd, J = 14.0, 5.5 Hz), 2.95 (1H, dd, J = 14.0, 9.5 Hz), 1.56
(3H, s), 1.42 (9H, s), 1.31 (3H, s); 13C NMR (125 MHz, CD3OD) δ
176.2, 174.0, 171.8, 169.8, 138.3, 136.5, 130.5, 130.3, 129.72, 129.70,
128.2, 128.0, 83.3, 73.1, 68.2, 65.6, 59.5, 55.8, 43.2, 38.3, 29.8, 28.3,
27.5; HRMS (ESI+) m/z calcd for C29H36N3O5S [M + H]+: 538.2370,
found 538.2347.
Amides Synthesized via General Procedure A. Representative
Procedure: (S)-Benzyl-2-((S)-2-((tert-butoxycarbonyl)amino)-2-
phenylacetamido)-3-methylbutanoate (14a).29 In a flame-dried
vial with a stir bar were loaded L-valine benzyl ester 13 (72.3 mg,
0.349 mmol, 1.0 equiv) and DMF (3 mL). The solution was cooled to
0 °C before the addition of lithium Boc-L-phenylglycine carboxylate
12a (99.0 mg, 0.385 mmol, 1.1 equiv), followed by HBTU (151.0 mg,
0.398 mmol, 1.1 equiv). The mixture was stirred at 0 °C for 24 h
before slowly warming to 10 °C (9 additional hours of reaction time).
The reaction mixture was then concentrated down to a thick residue
using an air stream, and then loaded directly onto a silica column.
Flash chromatography (3:1 hexanes:EtOAc) of the crude residue
afforded 14a (153.6 mg, quantitative yield) as an inseparable mixture
of diastereomers (dr 99:1 by HPLC). White foam; Rf 0.44 (3:1
hexanes:EtOAc); HPLC (C18 column, 4.6 × 250 mm (5 μm), 45%
H2O/MeCN, 0.5 mL/min, 23 °C, 210 nm, tR (L,L): 51.58 min, tR
(D,L): 54.44 min); [α]D21 +48.3 (c 1.00, CHCl3) [lit.29 [α]2D5 +26.8 (c
0.94, CHCl3)]; IR (thin film in CH2Cl2) νmax 3317, 2969, 1739, 1715,
1663, 1525, 1498, 1367, 1246, 1169 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.40 (10H, m), 6.24 (1H, d, J = 8.5 Hz), 5.71 (1H, br s),
5.17 (1H, br s), 5.10 (1H, d, J = 12.0 Hz), 5.05 (1H, d, J = 12.0 Hz),
4.55 (1H, dd, J = 8.5, 4.5 Hz), 2.22−2.10 (1H, m), 1.41 (9H, s), 0.90
(3H, d, J = 7.0 Hz), 0.83 (3H, d, J = 7.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 171.2, 170.3, 155.3, 137.9, 135.3, 129.1, 128.7, 128.58,
128.55, 128.4, 127.3, 80.3, 67.2, 58.9, 57.5, 31.5, 28.4, 19.0, 17.7;
HRMS (ESI+) m/z calcd for C25H33N2O5 [M + H]+: 441.2384, found
441.2386.
(S)-Benzyl-2-((S)-2-(((benzyloxy)carbonyl)amino)-2-phenyl-
acetamido)-3-methylbutanoate (14b).21a White solid (176.3 mg,
96%, dr 97:3 by HPLC); Rf 0.32 (3:1 hexanes:EtOAc); HPLC (C18
column, 4.6 × 250 mm (5 μm), 45% H2O/MeCN, 0.5 mL/min, 23
°C, 210 nm, tR (L,L): 54.78 min, tR (D,L): 59.52 min); [α]2D1 +53.2 (c
1.08, CHCl3); IR (thin film in CH2Cl2) νmax 3307, 2964, 1734, 1707,
1
1659, 1533, 1246, 1139 cm−1; H NMR (400 MHz, CDCl3) δ 7.42−
7.28 (13H, m), 7.27−7.22 (2H, m), 6.15 (1H, d, J = 8.5 Hz), 6.09−
5.98 (1H, br m), 5.30−5.20 (1H, br m), 5.15−4.98 (4H, m), 4.54 (1H,
dd, J = 8.5, 5.0 Hz), 2.23−2.10 (1H, m), 0.89 (3H, d, J = 7.0 Hz), 0.82
(3H, d, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 171.1, 169.9,
155.8, 137.6, 136.3, 135.2, 129.2, 128.74, 128.72, 128.6 (2C), 128.5,
128.24, 128.20, 127.4, 67.2 (2C), 59.0, 57.6, 31.5, 19.0, 17.7; HRMS
(ESI+) m/z calcd for C28H31N2O5 [M + H]+: 475.2227, found
475.2233.
(S)-tert-Butyl-3-phenyl-2-pivalamidopropanoate (16g). White
solid (242.1 mg, 84%); mp 71−72 °C (CH2Cl2); Rf 0.53 (4:1
hexanes:EtOAc); [α]2D3 +58.0 (c 1.33, CHCl3); IR (thin film in
CH2Cl2) νmax 3316 (br), 3071, 3031, 2977, 2934, 2871, 1722, 1645,
(S)-tert-Butyl-2-formamido-3-phenylpropanoate (16a).30 Color-
less oil (69.6 mg, 61% yield); Rf 0.20 (2:1 hexanes:EtOAc); [α]D23
+16.9 (c 1.20, EtOH) [lit.30 [α]2D5 +16.0 (c 0.7, EtOH)]; H NMR
1
1
1539, 1367, 1254, 1154 cm−1; H NMR (300 MHz, CDCl3) δ 7.31−
(300 MHz, CDCl3) δ 8.17 (1H, s), 7.33−7.20 (3H, m), 7.19−7.12
(2H, m), 6.11 (1H, br d, J = 6.0 Hz), 4.89−4.79 (1H, m), 3.16−3.06
(2H, m), 1.41 (9H, s); 13C NMR (75 MHz, CDCl3) δ 170.3, 160.5,
135.9, 129.6, 128.5, 127.2, 82.8, 52.4, 38.1, 28.1; HRMS (DART) mass
calcd for C14H20NO3 [M + H]: 250.1438, found 250.1446.
7.18 (3H, m), 7.17−7.10 (2H, m), 6.08 (1H, br d, J = 7.0 Hz), 4.73
(1H, ddd, J = 7.5, 6.0, 6.0 Hz), 3.14 (1H, dd, J = 14.0, 6.0 Hz), 3.07
(1H, dd, J = 14.0, 6.0 Hz), 1.42 (9H, s), 1.15 (9H, s); 13C NMR (75
MHz, CDCl3) δ 177.8, 171.0, 136.4, 129.7, 128.4, 127.0, 82.4, 53.3,
38.8, 38.0, 28.1, 27.5; HRMS (DART) mass calcd for C18H28NO3 [M
+ H]: 306.2064, found 306.2075.
(S)-tert-Butyl-2-(3-ethoxy-3-oxopropanamido)-3-phenyl-
propanoate (16b). Colorless oil (289.1 mg, quantitative yield); Rf
0.41 (2:1 hexanes:EtOAc); [α]2D3 +47.2 (c 0.94, CHCl3); IR (neat)
νmax 3375 (br), 3088, 3064, 3031, 2981, 2935, 1731, 1653, 1367, 1151,
(S)-tert-Butyl-2-acrylamido-3-phenylpropanoate (16h).32 Color-
less crystalline solid (76.7 mg, 61%); mp 35−36 °C (CH2Cl2); Rf 0.46
1
1033 cm−1; H NMR (300 MHz, CDCl3) δ 7.45 (1H, br d, J = 7.5
1
(2:1 hexanes:EtOAc); [α]D24 +116.3 (c 0.91, CHCl3); H NMR (300
Hz), 7.32−7.11 (5H, m), 4.75 (1H, ddd, J = 7.5, 6.0, 6.0 Hz), 4.18
(2H, q, J = 7.0 Hz), 3.32 (1H, d, J = 17.5 Hz), 3.26 (1H, d, J = 17.5
Hz), 3.17−3.04 (2H, m), 1.40 (9H, s), 1.26 (3H, t, J = 7.0 Hz); 13C
NMR (75 MHz, CDCl3) δ 170.4, 168.9, 164.6, 136.3, 129.6, 128.5,
127.1, 82.5, 61.7, 54.0, 41.5, 38.1, 28.1, 14.2; HRMS (DART) mass
calcd for C18H26NO5 [M + H]: 336.1806, found 336.1819.
MHz, CDCl3) δ 7.32−7.19 (3H, m), 7.18−7.11 (2H, m), 6.28 (1H,
dd, J = 17.0, 1.5 Hz), 6.16−6.02 (2H, m), 5.65 (1H, dd, J = 10.0, 1.5
Hz), 4.84 (1H, ddd, J = 8.0, 6.0, 6.0 Hz), 3.19−3.07 (2H, m), 1.41
(9H, s); 13C NMR (75 MHz, CDCl3) δ 170.7, 164.9, 136.2, 130.7,
129.7, 128.5, 127.1, 127.0, 82.7, 53.6, 38.1, 28.1; HRMS (DART) mass
calcd for C16H22NO3 [M + H]: 276.1594, found 276.1600.
(S)-tert-Butyl-2-(2-(2-methyl-1,3-dioxolan-2-yl)acetamido)-3-
phenylpropanoate (16c). White semisolid (280.1 mg, 90%); Rf 0.39
(1:1 hexanes:EtOAc); [α]D23 +26.9 (c 1.27, CHCl3); IR (thin film in
CH2Cl2) νmax 3377 (br), 2981, 2936, 2892, 1733, 1660, 1525, 1367,
1155, 1046 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.32−7.17 (5H, m),
6.91 (1H, br d, J = 7.5 Hz), 4.76 (1H, ddd, J = 7.5, 6.5, 6.5 Hz), 3.98−
3.89 (3H, m), 3.88−3.82 (1H, m), 3.11 (1H, dd, J = 14.0, 6.5 Hz),
(S)-tert-Butyl-2-((2E,4E)-hexa-2,4-dienamido)-3-phenyl-
propanoate (16i). White solid (204.0 mg, quantitative yield); mp
119−120 °C (CH2Cl2); Rf 0.32 (4:1 hexanes:EtOAc); [α]2D4 +170.2 (c
1.14, CHCl3); IR (thin film in CH2Cl2) νmax 3286 (br), 3028, 2978,
1
2933, 1733, 1660, 1635, 1615, 1538, 1367, 1153, 998 cm−1; H NMR
(300 MHz, CDCl3) δ 7.31−7.11 (6H, m), 6.21−6.01 (2H, m), 5.96
(1H, br d, J = 7.5 Hz), 5.74 (1H, d, J = 15.0 Hz), 4.85 (1H, ddd, J =
I
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7.5, 6.0, 6.0 Hz), 3.19−3.05 (2H, m), 1.83 (3H, d, J = 5.5 Hz), 1.40
(9H, s); 13C NMR (75 MHz, CDCl3) δ 170.9, 165.7, 141.8, 138.3,
136.4, 129.78, 129.73, 128.4, 127.0, 121.2, 82.5, 53.7, 38.3, 28.1, 18.7;
HRMS (ESI+) m/z calcd for C19H26NO3 [M + H]+: 316.1907, found
316.1910.
Amides Synthesized via General Procedure C. Representative
Procedure: (S)-tert-Butyl-2-(hept-2-ynamido)-3-phenylpropanoate
(18a). To a flame-dried 50 mL flask with a stir bar were loaded 1-
hexyne 17a (115 μL, 1.001 mmol) and THF (8 mL). The resultant
solution was cooled to −78 °C, and nBuLi (1.96 M in hexanes, 400 μL,
0.784 mmol) was added dropwise. After the addition was complete,
the solution was stirred at −78 °C for an additional 30 min. A small
piece of dry ice (weighing approximately 15 g) was placed into a 250
mL flask fitted with a drying tube (packed with drierite), and CO2 gas
was bubbled continually into the above solution at −78 °C for 30 min
before slowly warming to room temperature (30 min) with continued
bubbling. Caution!: A flask with sufficient head space must be used and
fitted with an exit bubbler prior to the addition of CO2 gas to avoid
overpressurizing the vessel, especially as it warms to room temperature.
After the solution was warmed to room temperature, the flow of CO2
was stopped and the solution was concentrated to dryness in vacuo to
yield the crude carboxylate. To this flask was added L-phenylalanine
tert-butyl ester hydrochloride 4 (258.6 mg, 1.003 mmol) and it was
(S)-tert-Butyl-2-methacrylamido-3-phenylpropanoate (16j).33
White solid (308.6 mg, 98%); mp 64−65 °C (CH2Cl2); Rf 0.39 (4:1
hexanes:EtOAc); [α]2D4 +69.6 (c 1.25, CHCl3) [lit.33 [α]D +64.7 (c 1.0,
CHCl3)]; IR (thin film in CH2Cl2) νmax 3349 (br), 2990, 2979, 1744,
1
1653, 1613, 1530, 1148, 940 cm−1; H NMR (400 MHz, CDCl3) δ
7.31−7.20 (3H, m), 7.18−7.12 (2H, m), 6.26 (1H, br d, J = 7.0 Hz),
5.67 (1H, dq, J = 1.0, 1.0 Hz), 5.33 (1H, qd, J = 1.5, 1.0 Hz), 4.80 (1H,
ddd, J = 7.0, 6.0, 6.0 Hz), 3.16−3.12 (2H, m), 1.94 (3H, dd, J = 1.5,
1.0 Hz), 1.42 (9H, s); 13C NMR (100 MHz, CDCl3) δ 170.8, 167.6,
139.8, 136.3, 129.7, 128.5, 127.1, 120.1, 82.6, 53.6, 38.0, 28.1, 18.6;
HRMS (DART) mass calcd for C17H24NO3 [M + H]: 290.1751, found
290.1756.
(S)-tert-Butyl-2-benzamido-3-phenylpropanoate (16k).34 Beige
crystalline solid (170.5 mg, quantitative yield); mp 76−78 °C
(CH2Cl2); Rf 0.74 (2:1 hexanes:EtOAc); [α]D24 +81.0 (c 1.49,
slurried in DMF (5 mL) before dropwise addition of Hunig’s base
̈
(200 μL, 1.149 mmol), followed by HBTU (388.0 mg, 1.023 mmol).
The crude reaction mixture was stirred for a further 1 h at room
temperature, and then concentrated down to a thick residue using an
air stream before being loaded directly onto a silica column. Flash
chromatography (4:1 hexanes:EtOAc) of the crude residue afforded
18a (249.6 mg, 97% yield) as a colorless oil; Rf 0.56 (4:1
hexanes:EtOAc); [α]D26 +84.4 (c 1.26, CHCl3); IR (neat) νmax 3295
(br), 3063, 3029, 2961, 2935, 2873, 2235, 1731, 1651, 1368, 1155
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.32−7.21 (3H, m), 7.19−7.13
(2H, m), 6.23 (1H, br d, J = 7.5 Hz), 4.77 (1H, ddd, J = 7.5, 6.0, 6.0
Hz), 3.16−3.06 (2H, m), 2.28 (2H, t, J = 7.0 Hz), 1.58−1.48 (2H, m),
1.46−1.36 (11H, m), 0.91 (3H, t, J = 7.5 Hz); 13C NMR (100 MHz,
CDCl3) δ 170.2, 152.9, 136.0, 129.7, 128.5, 127.1, 88.3, 82.8, 75.4,
53.9, 38.0, 29.8, 28.1, 22.1, 18.4, 13.6; HRMS (DART) mass calcd for
C20H28NO3 [M + H]: 330.2069, found 330.2069.
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.78−7.69 (2H, m), 7.54−
7.46 (1H, m), 7.45−7.36 (2H, m), 7.32−7.23 (3H, m), 7.22−7.14
(2H, m), 6.66 (1H, br d, J = 7.0 Hz), 4.96 (1H, ddd, J = 7.0, 5.5, 5.5
Hz), 3.30−3.16 (2H, m), 1.44 (9H, s); 13C NMR (75 MHz, CDCl3) δ
170.8, 166.9, 136.3, 134.2, 131.8, 129.7, 128.7, 128.5, 127.15, 127.09,
82.8, 54.0, 38.1, 28.1; HRMS (DART) mass calcd for C20H24NO3 [M
+ H]: 326.1751, found 326.1761.
(S)-tert-Butyl-2-(nicotinamido)-3-phenylpropanoate (16l). In a
flame-dried vial with a stir bar were loaded nicotinic acid sodium salt
15l (79.0 mg, 0.544 mmol), L-phenylalanine tert-butyl ester hydro-
chloride 4 (140.0 mg, 0.543 mmol), and DMF (4.0 mL). Hunig’s base
̈
(105 μL, 0.603 mmol) was added to the resulting solution dropwise,
followed by HBTU (215.0 mg, 0.567 mmol). The reaction mixture
was stirred for 1 h at room temperature, and then concentrated down
to a thick residue using an air stream before being loaded directly onto
a silica column. Flash chromatography (1:1 hexanes:EtOAc) of the
crude residue yielded an inseparable mixture of 16l and HOBt (235.0
(S)-tert-Butyl-3-phenyl-2-(3-(triisopropylsilyl)propiolamido)-
propanoate (18b). White solid (701.3 mg, 96%); mp 50−52 °C
(CH2Cl2); Rf 0.73 (4:1 hexanes:EtOAc); [α]2D5 +67.1 (c 1.05, CHCl3);
IR (thin film in CH2Cl2) νmax 3298 (br), 2944, 2866, 2164, 1733,
1662, 1496, 1368, 1257, 1224, 1154 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.31−7.21 (3H, m), 7.19−7.14 (2H, m), 6.29 (1H, br d, J =
8.0 Hz), 4.78 (1H, ddd, J = 8.0, 6.0, 5.5 Hz), 3.17−3.07 (2H, m), 1.40
(9H, s), 1.14−1.05 (21H, m); 13C NMR (100 MHz, CDCl3) δ 170.0,
152.0, 135.9, 129.7, 128.5, 127.2, 99.6, 89.3, 82.9, 54.0, 38.0, 28.1, 18.6,
11.1; HRMS (DART) mass calcd for C25H40NO3Si [M + H]:
430.2777, found 430.2784.
1
mg, approximately 25% w/w HOBt by H NMR). The mixture was
taken up in CHCl3 (5 mL) and sonicated for 1 min, producing a fine
white precipitate (HOBt) that was subsequently removed by filtration
over Celite directly into a 50 mL separatory funnel. Additional CHCl3
was added (15 mL), and the organic layer was washed twice with
saturated aqueous NaHCO3 (2 × 20 mL) and dried over MgSO4.
Concentration in vacuo afforded pure 16l (151.7 mg, 86% yield) as a
colorless oil; Rf 0.27 (1:1 hexanes:EtOAc); [α]2D3 −30.2 (c 1.16,
MeOH); IR (thin film in CH2Cl2) νmax 3325 (br), 2978, 1733, 1645,
1593, 1539, 1368, 1153 cm−1; 1H NMR (300 MHz, CD3OD; note: the
amide NH signal was not observed due to deuterium exchange) δ 8.86
(1H, d, J = 2.0 Hz), 8.66 (1H, dd, J = 5.0, 2.0 Hz), 8.14 (1H, ddd, J =
8.0, 2.0, 2.0 Hz), 7.51 (1H, dd, J = 8.0, 5.0 Hz), 7.33−7.17 (5H, m),
4.75 (1H, dd, J = 9.0, 6.0 Hz), 3.25 (1H, dd, J = 14.0, 6.0 Hz), 3.09
(1H, dd, J = 14.0, 9.0 Hz), 1.43 (9H, s); 13C NMR (75 MHz,
CD3OD) δ 172.3, 168.1, 152.9, 149.3, 138.6, 137.2, 131.9, 130.5,
129.6, 128.0, 125.2, 83.2, 56.7, 38.4, 28.3; HRMS (ESI+) m/z calcd for
C19H23N2O3 [M + H]+: 327.1703, found 327.1707.
(S)-tert-Butyl-2-(3-fluoropicolinamido)-3-phenylpropanoate
(16m). Colorless oil (132.6 mg, quantitative yield); Rf 0.39 (2:1
hexanes:EtOAc); [α]2D3 +55.4 (c 1.16, CHCl3); IR (thin film in
CH2Cl2) νmax 3385 (br), 2979, 1730, 1685, 1507, 1454, 1443, 1367,
1155 cm−1; 1H NMR (600 MHz, CDCl3) δ 8.38 (1H, ddd, J = 4.5, 1.5,
1.5 Hz), 8.32 (1H, br d, J = 8.0 Hz), 7.55 (1H, ddd, J = 10.0, 8.5, 1.5
Hz), 7.46 (1H, ddd, J = 8.5, 4.5, 4.0 Hz), 7.30−7.25 (2H, m), 7.24−
7.20 (3H, m), 4.95 (1H, ddd, J = 8.0, 6.0, 6.0 Hz), 3.26−3.17 (2H, m),
1.41 (9H, s); 13C NMR (150 MHz, CDCl3) δ 170.6, 161.9 (d, J = 6.0
Hz), 159.4 (d, J = 273.0 Hz), 144.2 (d, J = 6.0 Hz), 137.5 (d, J = 4.0
Hz), 136.5, 129.7, 128.5, 128.1 (d, J = 5.0 Hz), 127.0, 126.3 (d, J =
20.0 Hz), 82.5, 53.7, 38.5, 28.1; 19F NMR (564 MHz, CDCl3) δ
−119.2 (dd, J = 10.0, 4.5 Hz); HRMS (ESI+) m/z calcd for
C19H21FN2O3Na [M + Na]+: 367.1428, found 367.1431.
(2S)-tert-Butyl-3-phenyl-2-(4-((tetrahydro-2H-pyran-2-yl)oxy)but-
2-ynamido) propanoate (18c). Light yellow oil; (248.3 mg, 76%); Rf
0.33 (4:1 hexanes:EtOAc); [α]2D5 +59.7 (c 0.95, CHCl3); IR (neat)
νmax 3288 (br), 3030, 2941, 2243, 1733, 1652, 1520, 1155, 1122, 1079,
1028 cm−1 1H NMR (400 MHz, CDCl3; note: mixture of
;
diastereomers) δ 7.33−7.21 (3H, m), 7.19−7.13 (2H, m), 6.44−
6.24 (1H, br d, J = 7.5 Hz), 4.83−4.70 (2H, m), 4.41−4.29 (2H, m),
3.86−3.76 (1H, m), 3.59−3.49 (1H, m), 3.16−3.02 (2H, m), 1.88−
1.69 (2H, m), 1.68−1.48 (4H, m), 1.40 (9H, s); 13C NMR (100 MHz,
CDCl3; note: mixture of diastereomers) δ 169.9, 152.0, 135.8, 129.7,
128.6, 127.2, 97.40, 97.38, 83.0, 82.55, 82.52, 79.7, 62.19, 62.16, 54.0,
53.9, 38.0, 30.2, 28.1, 25.4, 19.02, 19.00; HRMS (DART) mass calcd
for C22H30NO5 [M + H]: 388.2124, found 388.2130.
(S)-tert-Butyl-2-(3-(cyclohex-1-en-1-yl)propiolamido)-3-phenyl-
propanoate (18d). Light yellow oil (292.4 mg, 95%); Rf 0.49 (4:1
hexanes:EtOAc); [α]D26 +71.6 (c 1.03, CHCl3); IR (neat) νmax 3292
(br), 3063, 3030, 2981, 2929, 2859, 2205, 1731, 1642, 1078, 1045,
1032 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.32−7.21 (3H, m), 7.20−
7.14 (2H, m), 6.37−6.33 (1H, m), 6.28 (1H, br d, J = 7.5 Hz), 4.79
(1H, ddd, J = 7.5, 6.0, 6.0 Hz), 3.18−3.06 (2H, m), 2.18−2.08 (4H,
m), 1.70−1.52 (4H, m), 1.40 (9H, s); 13C NMR (100 MHz, CDCl3) δ
170.2, 153.2, 140.7, 136.0, 129.7, 128.5, 127.1, 118.8, 87.5, 82.8, 80.7,
54.0, 38.1, 28.4, 28.1, 26.0, 22.1, 21.3; HRMS (DART) mass calcd for
C22H28NO3 [M + H]: 354.2069, found 354.2071.
J
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(S)-tert-Butyl-3-phenyl-2-(3-phenylpropiolamido)propanoate
(18e). White solid (294.9 mg, 84%); mp 87−88 °C (CH2Cl2); Rf 0.34
(4:1 hexanes:EtOAc); [α]D23 +96.8 (c 1.21, CHCl3); IR (thin film in
CH2Cl2) νmax 3288 (br), 3063, 3030, 2979, 2932, 2215, 1733, 1647,
(9) See, for example: Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.;
Wong, Y.-L.; Chen, H.-J.; Courtney, A. K.; Martin, S. F. J. Am. Chem.
Soc. 2002, 124, 8584−8592.
(10) Ficht, S.; Roglin, L.; Ziehe, M.; Breyer, D.; Seitz, O. Synlett
̈
1
1533, 1498, 1368, 1217, 1153 cm−1; H NMR (400 MHz, CDCl3) δ
2004, 2525−2528.
7.56−7.51 (2H, m), 7.45−7.39 (1H, m), 7.38−7.23 (5H, m), 7.22−
7.17 (2H, m), 6.44 (1H, br d, J = 7.5 Hz), 4.84 (1H, ddd, J = 7.5, 6.0,
6.0 Hz), 3.22−3.10 (2H, m), 1.42 (9H, s); 13C NMR (100 MHz,
CDCl3) δ 170.1, 152.8, 135.9, 132.7, 130.3, 129.7, 128.64, 128.58,
127.2, 120.2, 85.4, 83.0, 82.9, 54.1, 38.1, 28.1; HRMS (DART) mass
calcd for C22H24NO3 [M + H]: 350.1756, found 350.1759.
(11) Sakakura, T.; Choi, J.-C.; Yasuda, H. Chem. Rev. 2007, 107,
2365−2387.
(12) Duspara, P. A.; Batey, R. A. Angew. Chem., Int. Ed. 2013, 52,
10862−10866.
(13) Anderson, H. J.; Lee, S.-F. Can. J. Chem. 1965, 43, 409−414.
(14) Fringuelli, F.; Marino, G.; Savelli, G. Tetrahedron 1969, 25,
5815−5818.
(S)-tert-Butyl-3-phenyl-2-(3-(pyridin-3-yl)propiolamido)-
propanoate (18f). Light yellow oil (220.7 mg, quantitative yield); Rf
0.18 (2:1 hexanes:EtOAc); [α]2D3 +93.6 (c 1.02, CHCl3); IR (thin film
in CH2Cl2) νmax 3247 (br), 2978, 2220, 1730, 1646, 1534, 1368, 1152
(15) Stien, D.; Anderson, G. T.; Chase, C. E.; Koh, Y.-H.; Weinreb, S.
M. J. Am. Chem. Soc. 1999, 121, 9574−9579.
(16) Al-Mourabit, A.; Zancanella, M. A.; Tilvi, S.; Romo, D. Nat.
Prod. Rep. 2011, 28, 1229−1260 and references therein.
(17) The structures of side products 7 and 8 were synthesized
independently for confirmation. See the Supporting Information.
(18) Activated esters 6a and 6b were synthesized independently
through the coupling of 2 with HBTU or TPTU, respectively. See the
Supporting Information.
1
cm−1; H NMR (300 MHz, CDCl3) δ 8.76 (1H, d, J = 1.5 Hz), 8.62
(1H, dd, J = 5.0, 1.5 Hz), 7.82 (1H, ddd, J = 8.0, 2.0, 2.0 Hz), 7.36−
7.12 (6H, m), 6.58 (1H, br d, J = 8.0 Hz), 4.84 (1H, ddd, J = 8.0, 6.0,
6.0 Hz), 3.24−3.07 (2H, m), 1.43 (9H, s); 13C NMR (75 MHz,
CDCl3) δ 170.0, 153.1, 152.2, 150.4, 139.7, 135.8, 129.7, 128.6, 127.3,
123.3, 117.6, 85.8, 83.1, 81.7, 54.1, 38.0, 28.1; HRMS (ESI+) m/z calcd
for C21H23N2O3 [M + H]+: 351.1703, found 351.1702.
(19) Compound 6a was unambiguously determined to be the O-acyl
HOBt adduct via spectroscopic comparison with other known adducts.
For more information on O- versus N-acylation regiochemistry
observed in adduct formation, see: Brink, B. D.; DeFrancisco, J. R.;
Hillner, J. A.; Linton, B. R. J. Org. Chem. 2011, 76, 5258−5263.
(20) (a) Orito, K.; Miyazawa, M.; Nakamura, T.; Horibata, A.;
Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Yamazaki, T.;
Tokuda, M. J. Org. Chem. 2006, 71, 5951−5958. (b) Kondo, K.;
Murata, K.; Miyoshi, N.; Murai, S.; Sonoda, N. Synthesis 1979, 735−
736.
(21) (a) Ho, G.-J.; Emerson, K. M.; Mathre, D. J.; Shuman, R. F.;
Grabowski, E. J. J. J. Org. Chem. 1995, 60, 3569−3570. (b) Carpino, L.
A. J. Am. Chem. Soc. 1993, 115, 4397−4398.
(22) As a control to unambiguously establish the identities of the D,L
diastereomers of 14a,14b by 1H NMR and HPLC, the analogous
dipeptides were prepared by coupling racemic 11a,11b with the
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H, 13C, and 19F NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rbatey@chem.utoronto.ca. Phone/Fax: (416)-978-
5059.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
hydrochloride salt of 13 using HBTU and Hunig’s base.
̈
■
(23) The dr ratios for 14a,14b were measured by integration of the
The authors acknowledge financial support from a Natural
Science and Engineering Research Council (NSERC) of
Canada Discovery Grant and a Canadian Institutes of Health
Research Emerging Team Grants for R.A.B. and a PGS-D
scholarship to J.D.G.
1
CH3 signals of the L-valine residue in the crude H NMRs.
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