Facile ring opening reaction of oxazolone enables efficient amidation for aminoisobutyric acid

Article abstract of DOI:10.1007/s12272-018-1031-5

Abstract: 4,4-Dimethyloxazolones derived from N-protected aminoisobutyric acid (AIB) are particularly known as poor electrophiles due to the steric hindrance around the carbonyl and not employed as useful intermediates for amidation whereas numerous examp

Full text of DOI:10.1007/s12272-018-1031-5

Arch. Pharm. Res.
Online ISSN 1976-3786
Print ISSN 0253-6269
https://doi.org/10.1007/s12272-018-1031-5
RESEARCH ARTICLE
Facile ring opening reaction of oxazolone enables efficient
amidation for aminoisobutyric acid
Minmi Jo1 Sun-Woo Won1 Dong Guk Lee1 Jungeon Yun1 Sunhong Kim2
Young-Shin Kwak1
•
•
•
•
•
Received: 23 March 2018 / Accepted: 13 April 2018
Ó The Pharmaceutical Society of Korea 2018
Abstract 4,4-Dimethyloxazolones derived from N-pro-
tected aminoisobutyric acid (AIB) are particularly known
as poor electrophiles due to the steric hindrance around the
carbonyl and not employed as useful intermediates for
amidation whereas numerous examples have been reported
to support the utility of other oxazolones in amidation. AIB
is an important and strategical synthon in medicinal
chemistry but the peptide bond formation of the N-pro-
tected urethane derivatives of AIB is known to be often
unproductive due to the rapid formation of the stable 4,4-
dimethyloxazolone via an intramolecular cyclization. We
discovered that the 4,4-dimethyloxazolone of an AIB ure-
thane is in fact an excellent electrophile that enables effi-
cient amidation even with weakly reactive nucleophiles.
The 4,4-dimethyloxazolone can be stored in a pure form
and used as a reagent offering an efficient and convenient
synthetic tool for generating AIB-peptide analogs.
Graphical Abstract
Keywords Aminoisobutyric acid (AIB) Á 4,4-
Dimethyloxazolone Á Amidation Á Urea by-product
Introduction
Peptides offer a vast chemical space in drug discovery and
a myriad of therapeutic agents were developed based on
natural or unnatural peptide structures (Henninot et al.
2018; Wieland and Bodanszky 2012; Pekary 2013). Plasma
exposure level and duration time of peptide agents are most
affected by their ability resisting hydrolysis engaged by
endogenous proteolytic enzymes. Medicinal chemists
endeavor to employ unnatural amino acids bearing a bulky
substituent or a non-protogenic a-carbon in the peptide
design in order to overcome the metabolic hurdle. Ami-
noisobutyric acid (AIB) is therefore a very useful structural
motif in medicinal chemistry and often strategically
incorporated in drug molecules to enhance metabolic sta-
bility or induce tighter binding to biological target protein
(Fig. 1) (Frydman-Marom et al. 2011; Hansen et al. 1986).
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s12272-018-1031-5) contains supple-
mentary material, which is available to authorized users.
& Young-Shin Kwak
youngshin@korea.ac.kr
1
College of Pharmacy, Korea University, Sejong 30019, Korea
2
Disease Target Structure Research Center and Department of
Bioscience, Korea Research Institute of Bioscience and
Biotechnology, University of Science and Technology,
Daejeon 34141, Korea
123

M. Jo et al.
Fig. 1 Examples of
pharmaceutical agents bearing
AIB
Despite its utility in medicinal chemistry, peptide bond
formation with AIB is often found to be unproductive
because its carboxyl group is sterically very hindered by
the geminal dimethyl groups. Moreover, the reaction
intermediate from the commercial N-protected urethanes of
AIB undergoes an elusive formation of 4,4-dimethyloxa-
zolone as the byproduct and it is highly accelerated owing
to Thorpe-Ingold effect (Fig. 2) (Hroch et al. 2012; Kaneti
et al. 2004; Humphrey and Chamberlin 1997). In contrary
to the common knowledge that oxazolones are also useful
tools for peptide bond formation (Plucinska and Liberek
1987; Savage 2015), 4,4-dimethyloxazolones are particu-
larly classified as poor electrophiles for the purpose due to
steric hindrance. The troubles with amidating AIB get
aggravated when reactivity of the amine coupling partner is
sterically or electronically challenged.
recent work on an efficient amidation of AIB methyl ester (Jo
et al. 2018), herein we report a practical method of amidating
AIB by rediscovering the 4,4-dimethyloxazolone as a useful
coupling reagent.
Results and discussion
We set out our research by taking a commercial benzyl
urethane of AIB (Carboxybenzyl-AIB-OH, Cbz-AIB-OH)
in an ethylcarbodiimide(EDC)-mediated coupling condi-
tion with a highly reactive cyclohexylamine and monitored
the formation of the oxazolone and the amidation product.
As reported in literature a high percentage of 2-benzyloxy-
4,4-oxazolone (2) formation was observed and the desired
coupling product 1 was obtained only in less than 10%
yield (Scheme 2) even at elevated temperature up to 80 °C
in toluene. The similar product ratio was obtained with
other coupling reagents such as dicyclohexylcarbodiimide,
The unmet needs associated with AIB chemistry have
been recognized by Schafmeister’s group with a view to
circumvent the formation of the oxazolone byproduct and
develop a new amidation protocol for AIB. They found that
the acid fluoride derivative of Fluorenylmethyloxycar-
bonyl-protected AIB is free of the unproductive
intramolecular cyclization and reacts with amino acids to
afford the desired dipeptides. They hypothesized that the
reaction initially proceeds through an amino-anhydride
intermediate which rearranges to the desired peptide pro-
duct (Scheme 1) (Brown and Schafmeister 2008).
HATU
(hexafluorophosphate azabenzotriazole tetram-
ethyl uronium) and T3P (propylphosphonic anhydride).
We witnessed formation of 2 was very rapid indeed even at
- 78 °C and did not detect any starting acid by TLC
analysis at 2 min of the reaction. By treating Cbz-AIB-OH
only with EDC, 2 could be obtained consistently in near
quantitative yields and stored at ambient temperature.
With the readily available 2 in hand, we began to
question if 2 is an actual cul-de-sac of AIB amidation as
generally accepted and became much curious about its
reactivity and the potential utility for amidation. Since
2-aminothiazoles frequently serve to be key elements of
pharmacophores in medicinal chemistry, we proposed that
a coupling reaction with 2-aminothiazole should be a good
model study to set a standard for the reactivity of 2.
Therefore, we treated a purely isolated material of 2 with
While preparation of AIB-containing dipeptides has been
well addressed by the work, the examples of coupling part-
ners therein are limited to amino acids mechanistically and a
rather expensive solvent has to be used and the yields were
reported based only on HPLC analysis. We were prompted at
discovering an alternative protocol that enables a scalable
and more general synthesis of AIB-amides by using the AIB-
oxazolone formation to our advantage. In extension of our
Fig. 2 Formation of 4,4-
dimethyloxazolone during
amidation of AIB
123

Facile ring opening reaction of oxazolone enables efficient amidation…
Scheme 1 Precedent synthetic
methods in literature
Scheme 2 Rapid formation of
4,4-dimethyloxazolone under a
conventional amidation
condition
products more significantly in solvents more polar than
toluene. In the optimized condition, 2 was transformed in
toluene to the coupling product 3 after 3 h at 70 °C in a
91% isolated yield (Scheme 3).
With this evidence suggesting that 2 is rather a poten-
tially useful and reactive species for amidation, our atten-
tion was then attracted toward investigating other amine
nucleophiles. As a starting platform, we selected the
2-aminoazoles that are frequently employed in pep-
tidomimetic design hoping to validate the utility of 2 for
pharmaceutically valuable scaffolds. Under the same
reaction condition various 2-aminoazoles were tested and
the results are summarized in the Scheme 4. 2 responded to
the amine nucleophile’s electronic character in a very
straightforward manner. As demonstrated by the examples
4 and 5, substitution on the 2-aminothiazole ring by elec-
tron withdrawing groups negatively impacted the effi-
ciency of the reaction. By the same token, the reaction with
2-aminooxazole was less productive compared with
2-aminothiazole. Bicyclic 2-aminobenzoazoles, however,
were excellent nucleophiles and produced the
Scheme 3 A model study: reaction of 4,4-dimethyloxazolone with
2-aminothiazole using no other additive
the commercial 2-aminothiazole in different solvents using
no other additive. We were pleasantly surprised to observe
by TLC that the desired coupling product 3 started to form
even at room temperature. Mild heating was necessary to
completely consume 2 which, upon elevating temperature,
began to slowly decompose to unidentified multiple
123

M. Jo et al.
Scheme 4 Reaction of the
benzyloxyoxazolone 2 with
2-aminoazoles
corresponding coupling products 7–9 in very good yields.
Overall, the efficiency of the coupling reaction using 2 was
highly acceptable or rather very satisfactory for the class of
only moderately reactive nucleophiles.
opening of 2 occurred efficiently to give 13 and 14 in good
yields. 2-Aminopyridine also reacted with 2 faithfully and
produced 15 in 66% yield that is comparable or superior to
the reported yields reported for amidating 2-aminopyridine
using conventional methods (Xu et al. 2011; Priepke 2007).
Aliphatic amines were also tested using this protocol as
depicted in Scheme 6. The oxazolone 2 reacted almost quanti-
tatively with the cyclohexylamine that previously failed to react
with Cbz-AIB under the EDC-mediated coupling condition.
In the case of anilines, the electron withdrawing sub-
stituents did not significantly influence the productivity and
the coupling reaction afforded the desired amides in good
to excellent yields (Scheme 5). Even when we challenged
the reaction with various levels of steric hindrance, ring-
Scheme 5 Reaction of the
bezyloxyoxazolone 2 with
anilines
123

Facile ring opening reaction of oxazolone enables efficient amidation…
Scheme 6 Reaction of the
benzyloxyoxazolone 2 with
aliphatic amines
Other aliphatic amines carrying a large steric bulk such
as t-butylamine and diisopropylamine also successfully
produced the corresponding coupling adducts in 96 and
51% yields respectively. Amino acids were not sufficiently
soluble in toluene. In acetonitrile L-valine reacted with 2
and 18 was isolated in 44% yield. However, a reaction with
N-methyl-L-valine was not successful and it can be ascri-
bed to the extreme steric interaction between the two
reactants.
of 19 in deuterated toluene altering 2’s concentration. We
obtained a spectroscopic evidence of a bimolecular inter-
action between 19 and 2 as shown in Fig. 3. A proton of
19’s urea region notably reacted along with dose escalation
of 2 indicating an intermolecular hydrogen bond building
between the two molecules. We propose that the oxazolone
2 is stabilized through a 6-membered ring formation as
depicted below, which should account for the reduced
reactivity of 2 observed in Scheme 7.
Finally, we questioned why the conventional carbodi-
imide-mediated amidation has been unproductive and we
designed an experiment adding the urea 19 to the same
reaction that previously led 2 to form 1 in 92% yield
(Scheme 7). It turned out the presence of 19 suppressed the
reaction to almost none and the identical pattern was
observed with all the amine nucleophiles we tested with 2.
It suggested that carbodiimide-based amidations are
deterred unavoidably by its urea byproduct (Chen and
Turecek 2005). In order to elucidate the mechanism of this
unproductive event with 19, we followed 1H-NMR spectra
Materials and methods
General
All reactants or reagents were purchased from Sigma
Aldrich Co. or Tokyo Chemical Industry and used without
purification. Silica gel column chromatography was per-
formed with Silica Gel of Kieselgel 60 F254 plate(Merck).
1
All H NMR and 13C NMR spectra of organic products
Scheme 7 Observation of the
urea 19 deterring 2’s amidation
123

M. Jo et al.
Fig. 3 Evidence of an
interaction between 2 and 19 by
1H-NMR experiments and a
proposal for the bimolecular
adduct
were recorded on Bruker DPX 300 MHz or 600 MHz
Spectrometer. Data are reported as follows: chemical shift
in ppm (d), multiplicity (s = singlet, d = doublet, t =
triplet, m = multiplet), coupling constant (Hz), and inte-
gration. High-resolution mass spectra (HRMS) were
recorded on the Agilent 6530 Q-TOF mass spectrometer.
column chromatography on silica gel using n-heptane/
EtOAc as the eluents to afford compound (yield:
70 * 80%).
1H NMR (300 MHz, (CDCl3): d 7.45–7.35 (m, 5H),
5.322 (s, 2H), 1.47 (s, 6H); 13C NMR (75 MHz, CDCl3): d
178.8, 156.9, 134.1, 128.9, 128.6, 128.3, 71.5, 66.7, 25.2.
General procedure for transamidation
Benzyl (1-(cyclohexylamino)-2-methyl-1-oxopropan-2-
yl)carbamate (1)
Oxazolone (2; 0.251 mmol, 1 eq) and amine nucleophile
(0.326 mmol, 1.3 eq) was dissolved in toluene (1 mL) to a
concentration of 0.251 M. The reaction mixture was stirred
at 70 °C for 3 h, and concentrated in vacuo. The residue
was purified by flash column chromatography on silica gel
using n-heptane/EtOAc as the eluents to afford compound.
1H NMR (300 MHz, (CD3)2CO): d 7.38–7.31 (m, 5H),
6.84 (s, 1H), 6.55 (s, 1H), 5.05 (s, 2H), 3.65–3.62 (m, 1H),
1.794–1.66 (m, 4H), 1.47 (s, 6H), 1.38–1.08 (m, 6H); 13C
NMR (150 MHz, CDCl3): d 173.2, 155.1, 136.4, 128.6,
128.2, 128.1, 66.6, 56.8, 48.2, 32.8, 25.5, 24.7; HRMS
(ESI): m/z calcd for C18H26N2NaO3: 341.1841
[M ? Na]?; found: 341.1850.
Preparation of 2-benzyloxy-4,4-dimethyloxazolone
and spectral data of all compounds
Benzyl (2-methyl-1-oxo-1-(thiazol-2-ylamino)propan-2-
2-(Benzyloxy)-4,4-dimethyloxazol-5(4H)-one (2)
(Nakajima et al. 2016)
yl)carbamate (3)
1H NMR (300 MHz, (CD3)2CO): d 10.92 (s, 1H) 7.43 (d,
J = 3.6 Hz, 6H), 7.34 (s, 1H), 7.12 (d, J = 3.6 Hz, 1H),
6.85 (s, 1H), 5.06 (s, 2H), 1.61 (s, 6H); 13C NMR (75 MHz,
(CD3)2CO): d 172.9, 158.6, 155.2, 137.6, 137.0, 128.3,
128.1, 127.8, 113.1, 65.9, 56.7, 24.5; HRMS (ESI): m/z
calcd for C15H17N3NaO3S: 342.0888 [M ? Na]?; found:
342.0893.
Cbz-Aib-OH (2.107 mmol, 1 eq) and EDC (2.53 mmol,
1.2 eq) was dissolved in DCM (8 mL) to a concentration of
0.263 M. The reaction mixture was stirred at RT for 5 h,
and washed with water. The aqueous layer was extracted
with DCM (3 times) and the combined organic extracts
were washed with brine and dried over MgSO4. It was then
concentrated in vacuo. The residue was purified by flash
123

Facile ring opening reaction of oxazolone enables efficient amidation…
Benzyl (1-((5-bromothiazol-2-yl)amino)-2-methyl-1-
Benzyl (1-((1H-benzo[d]imidazol-2-yl)amino)-2-methyl-1-
oxopropan-2-yl)carbamate (4)
oxopropan-2-yl)carbamate (9)
1H NMR (300 MHz, (CD3)2CO): d 11.02 (s, 1H), 7.29 (s,
1H), 7.20 (s, 5H), 6.74 (s, 1H), 4.91 (s, 2H), 1.46 (s, 6H);
13C NMR (75 MHz, (CD3)2CO): 173.6, 159.0, 155.2,
138.6, 136.9, 128.3, 128.1, 127.8, 101.9, 66.0, 56.6, 24.41;
HRMS (ESI): m/z calcd for C15H16BrN3NaO3S: 419.9993
[M ? Na]?; found: 420.0010.
1H NMR (300 MHz, CDCl3): d 7.46–7.45 (m, 2H), 7.34 (s,
4H), 7.26–7.219 (m, 2H), 5.09 (s, 2H), 1.63 (s, 6H); 13C
NMR (150 MHz, CDCl3): d 177.8, 175.6, 154.7, 147.9,
135.9, 128.4, 128.2, 128.1, 122.3, 113.9, 67.1, 57.3, 25.1;
HRMS (ESI): m/z calcd for C19H20N4NaO3: 375.1433
[M ? Na]?; found: 375.1439.
Methyl 2-(2-(((benzyloxy)carbonyl)amino)-2-
Benzyl (2-methyl-1-oxo-1-(phenylamino)propan-2-
methylpropanamido)thiazole-5-carboxylate (5)
yl)carbamate (10)
1H NMR (300 MHz, (CD3)2CO): d 11.39 (s, 1H), 8.06 (s,
1H), 7.35 (s, 5H), 6.96 (s, 1H), 5.05 (s, 2H), 3.85 (s, 3H),
1.61 (s, 6H); 13C NMR (75 MHz, (CD3)2CO): d 173.7,
162.9, 162.0, 155.2, 144.8, 136.9, 128.3, 127.8, 127.6,
121.9, 66.0, 56.7, 51.4, 24.3; HRMS (ESI): m/z calcd for
C17H19N3NaO5S: 400.0943 [M ? Na]?; found: 400.0947.
1H NMR (300 MHz, (CD3)2CO): d 9.11 (s, 1H), 7.65 (d,
J = 0.9 Hz, 2H), 7.36–7.26 (m, 7H), 7.05 (t, J = 7.5 Hz,
1H), 6.70 (s, 1H), 5.07 (s, 2H), 1.57 (s, 6H); 13C NMR
(150 MHz, CDCl3): d 172.1, 155.7, 137.9, 135.9, 128.9,
128.6, 128.4, 128.3, 124.2, 119.9, 67.2, 57.9, 25.6; HRMS
(ESI): m/z calcd for C18H20N2NaO3: 335.1372
[M ? Na]?; found: 335.1378.
Benzyl (2-methyl-1-(oxazol-2-ylamino)-1-oxopropan-2-
yl)carbamate (6)
Benzyl (1-((4-chlorophenyl)amino)-2-methyl-1-oxopropan-
2-yl)carbamate (11)
1H NMR (300 MHz, CDCl3): d 9.76 (s, 1H), 7.44 (s, 1H),
7.35 (s, 5H) 6.99 (s, 1H), 5.12 (br s, 3H), 1.599 (s, 6H); 13
C
1H NMR (300 MHz, (CD3)2CO): d 9.28 (s, 1H), 7.67 (d,
J = 8.7 Hz, 2H), 7.36–7.30 (m, 7H), 6.74 (s, 1H), 5.06 (s,
2H), 1.55 (s, 6H); 13C NMR (150 MHz, CDCl3): d 172.2,
155.8, 136.5, 135.8, 129.1, 128.9, 128.6, 128.5, 128.3,
121.2, 67.3, 57.9, 25.6; HRMS (ESI): m/z calcd for C18-
H19ClN2NaO3: 369.0982 [M ? Na]? found: 369.0977.
NMR (75 MHz, (CD3)2SO): d 173.2, 155.3, 153.9, 137.3,
136.8, 128.7, 128.2, 128.1, 127.1, 65.7, 56.9, 25.2; HRMS
(ESI): m/z calcd for C15H17N3NaO4: 326.1117
[M ? Na]?; found: 326.1112.
Benzyl (1-(benzo[d]oxazol-2-ylamino)-2-methyl-1-
oxopropan-2-yl)carbamate (7)
Benzyl (2-methyl-1-oxo-1-((4-
(trifluoromethyl)phenyl)amino)propan-2-yl)carbamate (12)
1H NMR (300 MHz, (CD3)2CO): d 7.353 (s, 2H), 7.20 (br
s, 7H), 6.81 (s, 1H), 4.90 (s, 2H), 2.83 (s, 1H), 1.45 (s,
6H); 13C NMR (75 MHz, (CD3)2SO): d 172.9, 156.1,
155.4, 148.2, 141.2, 137.4, 128.7, 128.2, 128.1, 124.9,
124.0, 118.6, 110.4, 65.8, 57.3, 25.1; HRMS (ESI): m/z
calcd for C19H19N3NaO4: 376.1273 [M ? Na]?; found:
376.1279.
1H NMR (300 MHz, (CD3)2CO): d 9.53 (s, 1H), 7.88 (d,
J = 8.7 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 7.36 (s, 5H),
6.80 (s, 1H), 5.06 (s, 2H), 1.56 (s, 6H); 13C NMR (75 MHz,
(CD3)2CO): d 173.4, 155.1, 143.0, 137.1, 128.3, 127.8,
125.8, 125.7, 125.7, 125.6, 119.5, 65.8, 57.3, 24.6; HRMS
(ESI): m/z calcd for C19H19F3N2NaO3: 403.1245
[M ? Na]? found: 403.1243.
Benzyl (1-(benzo[d]thiazol-2-ylamino)-2-methyl-1-
oxopropan-2-yl)carbamate (8)
Benzyl (2-methyl-1-(methyl(phenyl)amino)-1-oxopropan-2-
yl)carbamate (13)
1H NMR (300 MHz, (CD3)2CO): d 7.95 (d, J = 8.4 Hz,
1H), 7.72 (d, J = 8.1 Hz, 1H), 7.46–7.29 (m, 7H), 6.94 (s,
1H), 5.07 (s, 2H), 1.65 (s, 6H); 13C NMR (75 MHz,
CDCl3): d 172.7, 158.2, 155.5, 148.3, 135.5, 132.2, 128.6,
128.4, 128.4, 126.2, 123.9, 121.4, 120.9, 67.6, 57.4, 25.3;
HRMS (ESI): m/z calcd for C19H19N3NaO3S: 392.1045
[M ? Na]?; found: 392.1055.
1H NMR (300 MHz, (CD3)2CO): d 7.34–7.23 (m, 10H),
6.04 (s, 1H), 4.99 (s, 2H), 3.18 (s, 3H), 1.48 (s, 6H); 13C
NMR (150 MHz, CDCl3): d 173.2, 154.0, 144.5, 136.4,
129.3, 128.5, 128.4, 128.2, 127.8, 127.6, 66.3, 57.8, 41.3,
27.2; HRMS (ESI): m/z calcd for C19H22N2NaO3:
349.1528 [M ? Na]? found: 349.1538.
123

M. Jo et al.
Benzyl (1-((2,6-dimethylphenyl)amino)-2-methyl-1-
Conclusion
oxopropan-2-yl)carbamate (14)
In summary, we believe that it is necessary to reconsider
the 4,4-dimethyloxazolone 2 as rather a highly available,
storable and synthetically very useful substrate for ami-
dating AIB. We demonstrated that a wide range of nucle-
ophilicity and steric bulk in amine nucleophiles was
compatible with 2 attesting to its synthetic utility in AIB
chemistry. It’s worth to note that, by the nature of the
reaction, only minimal purification is needed for this pro-
tocol and the procedure is in many aspects advantageous
and convenient particularly for medicinal chemists who
routinely generate many analogs at a time. We envision
that the findings described in this work would serve to
position 2 as a new reaction partner for amidating AIB.
1H NMR (300 MHz, (CD3)2CO): d 8.57 (s, 1H), 7.39–7.33
(m, 5H), 7.04 (s, 3H), 6.75 (s, 1H), 5.09 (s, 2H), 2.19 (s,
6H), 1.64 (s, 6H); 13C NMR (75 MHz, (CD3)2CO): d
172.5, 155.0, 137.2, 136.0, 135.1, 128.3, 127.8, 127.7,
127.6, 126.5, 65.7, 56.9, 25.0, 17.7; HRMS (ESI): m/z
calcd for C20H24N2NaO3: 363.1685 [M ? Na]? found:
363.1690.
Benzyl (2-methyl-1-oxo-1-(pyridin-2-ylamino)propan-2-
yl)carbamate (15)
1H NMR (300 MHz, (CD3)2CO): d 9.11 (s, 1H), 8.29 (d,
J = 3.9 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.73 (t,
J = 8.1 Hz, 1H), 7.35 (br s, 5H), 7.11–7.07 (m, 1H), 6.91
(s, 1H), 5.08 (s, 2H), 1.61 (s, 6H); 13C NMR (75 MHz,
(CDCl3): d 172.8, 155.1, 151.4, 147.7, 138.3, 135.9, 128.5,
128.2, 128.2, 119.8, 113.9, 67.2, 57.7, 25.5; HRMS (ESI):
m/z calcd for C17H19N3NaO3: 336.1324 [M ? Na]?;
found: 336.1327.
Acknowledgements This research was supported by the Basic
Research Program through the National Research Foundation of
Korea (NRF) funded by the Ministry of Education, Science and
Technology (NRF-2015R1A2A2A04003471).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Benzyl (1-(tert-butylamino)-2-methyl-1-oxopropan-2-
yl)carbamate (16)
1H NMR (300 MHz, (CD3)2CO): d 7.38-7.34 (m, 5H), 6.56
(s, 2H), 5.07 (s, 2H), 1.45 (s, 6H), 1.28 (s, 9H)); 13C NMR
(150 MHz, CDCl3): d 173.4, 155.0, 136.4, 128.5, 128.2,
128.1, 66.5, 57.2, 50.9, 28.5, 25.5; HRMS (ESI): m/z calcd
for C16H24N2NaO3: 315.1685 [M ? Na]?; found: 315.1689.
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Benzyl (1-(diisopropylamino)-2-methyl-1-oxopropan-2-
yl)carbamate (17)
1H NMR (300 MHz, (CD3)2CO): d 7.42–7.30 (m, 5H),
5.47 (s, 1H), 5.07 (s, 2H), 3.79 (m, J = 6.9 Hz, 2H), 1.47
(s, 6H), 1.21 (d, J = 6.9 Hz, 9H); 13C NMR (75 MHz,
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