A bio-inspired approach to proline-derived 2,4-disubstituted oxazoles

Article abstract of DOI:10.1515/hc-2017-0235

A convenient four-step approach to the synthesis of (S)-4-alkyl-2-(pyrrolidin-2-yl)oxazoles starting from l-Boc-proline inspired by naturally occurring oxazole-containing peptidomimetics is described. The key step is the cyclization of 1-Boc-N-(1-oxoalkan

Full text of DOI:10.1515/hc-2017-0235

Heterocycl. Commun. 2018; aop
Evgeniy Y. Slobodyanyuk, Oleksiy S. Artamonov, Irene B. Kulik, Eduard Rusanov,
Dmitriy M. Volochnyuk and Oleksandr O. Grygorenko*
A bio-inspired approach to proline-derived
2,4-disubstituted oxazoles
https://doi.org/10.1515/hc-2017-0235
a ‘biomimetic’ approach to the synthesis of 1 has been used,
Received September 13, 2017; accepted November 27, 2017
including the formation of oxazoline 2 and its subsequent
aromatization (Scheme 1) [7–23]. However, this method is
effective only when the substituent R1 in the oxazole ring
formed is an electron-withdrawing group (e.g. R1ꢀ=ꢀCO2Me).
Even for R1ꢀ=ꢀPh, the aromatization step requires harsh
conditions (NiO2, 150°C, μW) [13]. Recently, an alternative
approach has been reported for the preparation of the com-
pounds 1 with primary amino group (R3ꢀ=ꢀH), which is based
on oxidation of phthaloyl derivatives of the type 3 (R1ꢀ=ꢀH,
Ph, Bn; R2ꢀ=ꢀi-Pr; R3/PGꢀ=ꢀphthaloyl) with the Dess-Martin
reagent, followed by cyclodehydration and deprotection
[6]. Apart from the limited scope, the method offers a mod-
Abstract: A convenient four-step approach to the synthe-
sis of (S)-4-alkyl-2-(pyrrolidin-2-yl)oxazoles starting from
l-Boc-proline inspired by naturally occurring oxazole-
containing peptidomimetics is described. The key step
is the cyclization of 1-Boc-N-(1-oxoalkan-2-yl)pyrrolidine-
2-carboxamides – aldehyde intermediates which demon-
strate low to moderate stability – under Appel reaction
conditions. This method furnishes the target compounds
with more than 98% ee and in a 17–51% overall yield and
has been used at up to a 45-g scale.
Keywords: conformational restriction; heteroaliphatic; lead- erate yield of the key step (34–50%) and can be used only
oriented synthesis; oxazoles; peptidomimetics; synthesis.
at a milligram scale. Moreover, partial racemization occurs
upon removal of the phthalimide protective group.
In this work, we have taken inspiration from the
‘biocore’ concept described by Kombarov and co-workers
[24]. This concept refers to a combination of (hetero)ali-
phatic and hydrophilic aromatic rings providing privileged
Introduction
Since their isolation from marine products in the late 1980s, structures for drug discovery (Figure 1). Analysis of the
oxazole-containing peptidomimetics have been studied literature data published on ‘biocores’ obtained by a com-
extensively by synthetic organic and medicinal chemists bination of oxazole and common heteroaliphatic amines
[1–5]. It is believed that many of these natural products are (pyrrolidine/piperidine) shows that 2-(2-pyrrolidinyl)oxa-
derived from enzymatic post-translational modifications of zoles 4 are most often encountered in papers and patents
peptide-based precursors containing serine or threonine [25]. As in the case of the general structure 1, however,
moieties [2]. It is not surprising, therefore, that 2,4-disubsti- nearly all known compounds 4 are substituted with R1ꢀ=ꢀaryl
tuted oxazoles of general formula 1 derived from α-amino or CO2R, or are derived from them [7–12, 21–23].
acids have attracted much attention as promising building
Here, we describe the multigram synthesis of oxazole-
blocks for drug discovery [6–13] or total synthesis of natural substituted pyrrolidines 4 with aliphatic substituents at
products including plantazolicins [14, 15], telomestatin C-4 position (R1ꢀ=ꢀH, alkyl; R2ꢀ=ꢀH) starting from enantio-
[16], ulapualides [17, 18] and diazonamide A [19, 20] and as pure (S)-N-Boc-proline (5 in Figure 1) [26]. Instant JChem
ligands for enantioselective catalysis [21, 22]. In most cases, was used for the prediction of the physico-chemical
properties of the compounds. Conformational restriction
provided by the saturated heteroaliphatic ring of 4 and
an improved hydrophilicity are valuable features in lead-
*Corresponding author: Oleksandr O. Grygorenko, National Taras
oriented synthesis in medicinal chemistry [27, 28].
Shevchenko University of Kyiv, Volodymyrska Street, 64, Kyiv 01601,
Ukraine; and Enamine Ltd., Chervonotkatska 78, Kyiv 02094,
Ukraine, e-mail: gregor@univ.kiev.ua
R1
R1
R1
H
Evgeniy Y. Slobodyanyuk, Oleksiy S. Artamonov, Eduard Rusanov
and Dmitriy M. Volochnyuk: Institute of Organic Chemistry, National
Academy of Sciences of Ukraine, Kyiv 02660, Ukraine
R2
N
PG
R3
PG
N
N
R2
N
R3
N
R2
N
R3
-H2O
H
O
O
O
OH
3
2
1
Irene B. Kulik: Institute of Bioorganic Chemistry and Petrochemistry,
National Academy of Sciences of Ukraine, Kyiv 02660, Ukraine
Scheme 1ꢀBiomimetic approach to oxazole building blocks.
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2ꢀ
ꢀE.Y. Slobodyanyuk et al.: Proline-derived 2,4-disubstituted oxazoles
O
(Hetero)
aliphatic
ring
Hydrophilic
heteroaromatic
ring
CO2H
N
H
N
N
Boc
R1
4 : R1 = H, alkyl
5
‘Biocore’
Figure 1ꢀ‘Biocore’ concept and its implementation into the target compounds 4.
Results and discussion
7a–f were obtained with overall yields of 60–86%. The
procedure did not require chromatographic purification
Our strategy for the preparation of the secondary amines and was amenable to a multigram scale-up.
4a–e was related to the ‘biomimetic’ approaches shown
The next step, oxidation of 7 to aldehydes 9, was per-
in Scheme 1. Initially, the synthesis followed the literature formed first with the Dess-Martin reagent, by analogy with
analogs and involved dipeptides 6, which were prepared the literature examples [6, 29] and our previous in-house
from 5 in an 85–95% yield using the mixed anhydride experience. It was found that in the case of 7a, the yield
activation method (Scheme 2) [29]. However, reduction of the product 9a varied significantly in different experi-
of 6a–e with NaBH4 was accompanied by a problematic ments [35–70% by 1H nuclear magnetic resonance (NMR)].
isolation of the target products 7a–e, which was related Moreover, the product 9a showed limited storage stabil-
to their high aqueous solubility and formation of stable ity. A detailed investigation revealed that the Swern reac-
boron complexes. Although compounds of 7 were isolated tion [dimethyl sulfoxide (DMSO), (COCl)2, Et3N, −60°C, 1 h]
in a 50–85% yield, the attempted scaling up of this pro- gives more reproducible results, and the crude products
1
cedure was not successful. Therefore, we switched to a 9a–d were obtained in a 55–85% yield (by H NMR). In
one-step synthesis of 7 directly from 5 using coupling with the case of 7e (R1ꢀ=ꢀH), the use of the Dess-Martin reagent
β-amino alcohols 8 (either commercially available or pre- appeared to be more fruitful than the Swern oxidation
1
pared from the corresponding α-amino acids). Products (35% vs. 5% yield of 9e by H NMR). Unfortunately, the
R1
O
O
H2N
O
O
O
O
iBuO
Cl
R1
O
O
N
Boc
N
N
HN
OH
DIPEA
DIPEA
OiBu
O
Boc
85−95%
Boc
5
O
6a–e
a: R1 = Me, R2 = H
b: R1 = i-Pr, R2 = H
c: R1 = i-Bu, R2 = H
H2N
R1
NaBH4
50−85%
, DIPEA
R2
8a–g
OH
O
d: R1 = t-Bu, R2 = H
e: R1 = R2 = H
R1
50−60%
N
Boc
HN
f: R1 = Ph, R2 = H
OH
g: R1 = H, R2 = CH2OH
R2
7a–g
Dess-Martin reagent or
NaIO4
(for 7g)
DMSO, (COCl)2, Et3N
(for 7a–f)
O
O
R1
HCl
2Cl
C2Cl6, PPh3
O
R1
N
O
N
Et2O, MeOH
R1
35−72% (from
7a–d or 7g)
N
H
N
N
N
+
H2
H+
Boc
Boc
11a–e
76−85%
4a–e · 2HCl
9a–f
Scheme 2ꢀSynthesis of the compounds 4a–eꢁ·ꢁ2HCl.
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ꢂ3
E.Y. Slobodyanyuk et al.: Proline-derived 2,4-disubstituted oxazolesꢂ
product 9f (R1ꢀ=ꢀPh) could not be obtained at all using
either method.
It was shown that the storage stability of products
9a–e is strongly affected by the steric volume of the sub-
stituent R1. In particular, the product 9a has limited sta-
bility in CH2Cl2 solution (ca. 1 h) and as a neat product at
−24°C (ca. 8 h). On the contrary, compounds 9b–d with
relatively bulky alkyl substituents are relatively stable
in both cases (at least for 24 h). The product 7e is rather
unstable either in CH2Cl2 solution or as a neat compound
at −24°C (less than 1 h). Other factors influencing the sta-
bility of 9a–e include temperature which should be kept
below 20°C during all manipulations with 9 including
the evaporation of the solvent. It can be suggested that
the stability of the products 9a–f is also related to their
reactivity toward self-condensation, which is diminished
upon an increase in the size of the alkyl substituent R1.
In the case of R1ꢀ=ꢀPh, this side reaction becomes espe-
cially fast, presumably due to a concomitant increase in
the acidity of α-CH adjacent to the aldehyde moiety. It was
apparent that the use of acidic or basic reagents should be
avoided during the synthesis of 9e, which might improve
the yield of this product. For this reason, we have synthe-
sized amide 7g (60% yield) and subjected it to oxidative
cleavage with NaIO4. Using this procedure, the product 9e
was obtained in a 45% yield.
Figure 2ꢀMolecular structure of compound 11a.
1H NMR and 19F NMR analyses. In addition, the enanti-
omer of compound 11c was synthesized from D-N-Boc-
proline and used as a control for chiral stationary phase
high-performance liquid chromatography (HPLC). It was
found that enantiopure product 11c showed no detect-
able peak of its enantiomer in the chromatogram [≥98%
ee, (ChiralPack® IA column, hexanes – 2-propanol (95:5)
as an eluent]. Under the same conditions, single peaks
(≥98% ee) were also observed in the chromatograms of
other products 11.
Taking into account the low stability of aldehydes 9,
the crude products 9 were used immediately in the next
step, which is the dehydrative oxazole ring formation.
The Appel reaction was used for this reason, by analogy
with the literature results published previously [6, 29]. Conclusions
It was found that the use of the CBr4-PPh3 system gave a
1
low yield of the target products 11 (less than 20% by H Synthesis of (S)-4-alkyl-2-(pyrrolidin-2-yl)oxazoles was
NMR), whereas with C2Cl6-PPh3, the oxazoles 11a–e were performed starting from l-Boc-proline and using an
obtained in a 50–90% yield.
approach inspired by biosynthesis of oxazole-containing
The structure of compound 11a was confirmed by peptidomimetics isolated from natural products. Optimi-
X-ray single crystal analysis (CCDC-1570445 [30], Figure 2). zation of the procedures was performed for each step, in
It should be noted that only one enantiomer of 11a was order to make the method scalable. It was shown that the
observed in the crystal structure.
key intermediates, 1-Boc-N-(1-oxoalkan-2-yl)pyrrolidine-
In the final step of the synthesis, deprotection of com- 2-carboxamides (9), demonstrate low to moderate stabil-
pounds 11a–e was performed by treatment with HCl. It was ity, which is increased with the increasing size of the alkyl
found that using a solution of HCl in Et2O resulted in pre- group near the aldehyde moiety. Therefore, it is strongly
cipitation of 11ꢀ·ꢀHCl, so that a complete conversion could recommended to submit them to the next step immedi-
not be achieved. Fortunately, the use of HCl in Et2O-MeOH ately after isolation.
furnished the target products 4a–e as dihydrochlorides in
The target products were obtained in only four steps
a 76–85% yield. It should be noted that the method can be from derivatives of natural α-amino acids in a 17–51%
used for the synthesis of up to 45 g of the products 4ꢀ·ꢀ2HCl overall yield, with ≥98% ee and at up to a 45-g scale. The
in a single run.
overall yield of the product is increased upon an increase
To analyze the optical purity of the products, com- in the lipophilicity of the compound and hence follows
pound 4aꢀ·ꢀ2HCl was derivatized with the Mosher’s the ‘LogP drift’ effect proposed by Churcher and co-work-
reagent, which gave a single diastereomer according to ers (Figure 3) [27]. In our opinion, this effect might be
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4ꢀ ꢀE.Y. Slobodyanyuk et al.: Proline-derived 2,4-disubstituted oxazoles
residue was triturated with Et2O (400 mL), filtered, washed with Et2O
(200 mL) and then with H2O (100 mL). As the product is water solu-
ble, it is necessary to use a minimal amount of H2O at this step. The
product 7 was dried under reduced pressure.
tert-Butyl (S)-2-[((S)-1-hydroxypropan-2-yl)carbamoyl]-pyrroli-
dine-1-carboxylate (7a)ꢁYield 62.9 g (63%); white solid; mp 175–
+
1
178°C; MS: m/z 295 (MNa ); H NMR (CDCl3): δ 6.82 (br s, 0.68H, NH)
and 6.23 (br s, 0.32H, NH), 4.24 (br s, 1H), 4.02 (br s, 1H), 3.78–3.58
(m, 1H), 3.58–3.24 (m, 4H), 2.35–1.74 (m, 4H), 1.46 (s, 9H), 1.15 (d,
Jꢀ=ꢀ6.4 Hz, 3H); 13C NMR (CDCl3): δ 172.1, 155.3, 80.3, 66.1, 60.8 and 59.9,
47.5, 46.8, 30.9, 28.1, 24.3 and 23.5, 16.7. Anal. Calcd for C13H24N2O4: C,
57.33; H, 8.88; N, 10.29. Found: C, 57.06; H, 8.77; N, 10.19.
Figure 3ꢀOverall yields of products 4a–eꢁ·ꢁ2HCl as a function of their
tert-Butyl (S)-2-[((S)-1-hydroxy-3-methylbutan-2-yl)carbamoyl]
pyrrolidine-1-carboxylate (7b)ꢁYield 96.7 g (86%); white solid; mp
lipophilicity.
+
1
112–115°C; MS: m/z 301 (MH ); H NMR (CDCl3): δ 6.93 (br s, 0.77H)
and 6.28 (br s, 0.33H), 4.30 (br s, 1H), 3.75–3.65 (m, 2H), 3.59 (br s,
1H), 3.52–3.27 (m, 2H), 3.24–2.43 (m, 1H), 2.40–1.65 (m, 5H), 1.46 (s,
9H), 0.93 (d, Jꢀ=ꢀ6.8 Hz, 3H), 0.90 (d, Jꢀ=ꢀ6.8 Hz, 3H); 13C NMR (CDCl3):
δ 172.2, 155.4 and 154.3, 80.3, 63.3, 61.0 and 60.0, 56.8, 46.8, 30.8, 28.6
and 28.1, 24.3 and 23.5, 19.4, 18.1. Anal. Calcd for C15H28N2O4: C, 59.97;
H, 9.40; N, 9.33. Found: C, 59.80; H, 9.61; N, 9.10.
related to isolation issues observed for more hydrophilic
compounds.
In conclusion, (S)-4-alkyl-2-(pyrrolidin-2-yl)oxazoles
can be considered as building blocks readily available to
the chemical community. We believe that synthetic acces-
sibility and favorable physico-chemical characteristics
of these oxazole-derived ‘biocores’ make them valuable
starting points for early drug discovery.
tert-Butyl (S)-2-[((S)-1-hydroxy-4-methylpentan-2-yl)carbamoyl]
pyrrolidine-1-carboxylate (7c)ꢁYield 76.2 g (82%); white solid; mp
+
+
1
99–102°C; MS: m/z 337(MNa ), 315 (MH ); H NMR (CDCl3): δ 6.75 (br
s, 0.66H) and 6.17 (br s, 0.34H), 4.23 (br s, 1H), 3.97 (br s, 1H), 3.62 (br
s, 1H), 3.56–2.89 (m, 4H), 2.33–1.73 (m, 4H), 1.65–1.52 (m, 1H), 1.44 (s,
9H), 1.38–1.21 (m, 2H), 0.89 (d, Jꢀ=ꢀ6.6 Hz, 3H), 0.87 (d, Jꢀ=ꢀ6.6 Hz, 3H);
13C NMR (CDCl3): δ 172.1, 155.3 and 154.21, 80.3, 65.5, 60.8 and 60.0,
49.9, 46.8, 39.8, 30.8, 28.1, 24.6 and 23.5, 22.9, 21.8. Anal. Calcd for
C16H30N2O4: C, 61.12; H, 9.62; N, 8.91. Found: C, 61.07; H, 9.49; N, 9.01.
Experimental
Solvents were purified according to standard procedures [31]. Com-
pounds 6a–e [29], 8b–d and 8f [32] were prepared using reported
methods. All other starting materials were purchased from com-
mercial sources. Analytical thin-layer chromatography (TLC) was
performed using Polychrom SI F254 plates. Column chromatography
was performed using Kieselgel Merck 60 (230–400 mesh) as the sta-
tionary phase. NMR spectra were recorded on a Bruker 170 Avance
500 spectrometer (500 MHz for 1H and 125 MHz for 13C). Signal assign-
tert-Butyl (2S)-2-[(1-hydroxy-3,3-dimethylbutan-2-yl)carbamoyl]
pyrrolidine-1-carboxylate (7d)ꢁYield 90.4 g (84%); white solid; mp
+
+
122–125°C; MS: m/z 337 (MNa ), 315 (MH ); 1H NMR (CDCl3): δ 6.99 (br
s, 0.85H) and 6.27 (br s, 0.15H), 4.33 (br s, 1H), 3.91–3.68 (m, 2H), 3.60–
3.23 (m, 3H), 2.84 (s, 0.77H) and 2.53 (s, 0.23H), 2.43–1.81 (m, 4H), 1.47
(s, 9H), 0.92 (s, 9H); 13C NMR (CDCl3): δ 172.3, 155.5, 80.4, 62.7, 61.1, 60.0
and 59.6, 46.9, 33.1, 30.7, 28.1, 26.6, 24.4. Anal. Calcd for C16H30N2O4: C,
61.12; H, 9.62; N, 8.91. Found: C, 60.74; H, 9.92; N, 8.95.
1
1
ments for compounds 4a–eꢀ·ꢀ2HCl were made using H- H correla-
tion spectroscopy (COSY), heteronuclear single quantum coherence
(HSQC) and heteronuclear multiple bond correlation (HMBC) experi-
ments. Mass spectra were recorded on an Agilent 1100 LC/MSD SL
instrument [atmospheric pressure electrospray ionization (APESI)].
The stability of aldehydes 9 in CH2Cl2 solution or as neat products
tert-Butyl (S)-2-[(2-hydroxyethyl)carbamoyl]pyrrolidine-1-car-
boxylate (7e)ꢁYield 63.0 g (65%); white solid; mp 157–159°C (lit. [33]
mp 157–158°C). All other spectral and physical data are in accordance
with the literature.
1
at −24°C was studied by recording H NMR spectra for the aliquots
hourly; the compound was assumed to be stable if the relative inten-
sity of the aldehyde signal changed by no more than 10%.
tert-Butyl (S)-2-[((S)-2-hydroxy-1-phenylethyl)carbamoyl]pyrro-
lidine-1-carboxylate (7f)ꢁYield 85.2 g (78%); white solid; mp 121–
General procedure for synthesis of amides 7a–g
+
1
124°C; MS: m/z 334 (MH ); H NMR (CDCl3): δ 7.54 (br s, 0.45H) and
6.74 (br s, 0.55H), 7.48–6.97 (m, 5H), 5.05 (br s, 1H), 4.45–4.12 (m, 1H),
Isobutyl chloroformate (41.2 g, 0.30 mol or methyl chloroformate) 4.00–3.66 (m, 2H), 3.59–3.06 (m, 2H), 2.95 (br s, 1H), 2.50–1.65 (m, 4H),
was added dropwise to a solution of l-Boc-proline (65.0 g, 0.30 mol) 1.45 (s, 9H); 13C NMR (CDCl3): δ 172.4, 156.0 and 154.8, 139.1, 128.7, 127.6,
and N,N-diisopropylethylamine (DIPEA) (42.6 g, 0.33 mol) in anhy- 126.7 and 126.6, 80.7 and 80.6, 66.4 and 66.1, 61.2 and 60.2, 55.7, 47.1,
drous CH2Cl2 (1200 mL) at 0°C. After 1 h at room temperature, the 30.9, 28.3, 24.6 and 23.8. Anal. Calcd for C18H26N2O4: C, 64.65; H, 7.84;
mixture was cooled to −15°C and then amino alcohol 8 (0.33 mol) N, 8.38. Found: C, 64.50; H, 7.69; N, 8.37.
and DIPEA (42.6 g, 0.33 mol) were added in one portion. The mix-
ture was slowly warmed to room temperature and stirred overnight. tert-Butyl
(2S)-2-[(2,3-dihydroxypropyl)carbamoyl]pyrroli-
The volatiles were removed under reduced pressure, and the solid dine-1-carboxylate (7g)ꢁThe product was obtained according to
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E.Y. Slobodyanyuk et al.: Proline-derived 2,4-disubstituted oxazolesꢂ
the general procedure except for the work-up step. The mixture was
General procedure for synthesis of oxazoles 11a–e
concentrated under reduced pressure and the residue was purified
by column chromatography using CHCl3/MeOH (14:1) as an eluent
to give the pure compound as a clear viscous oil which solidified
overnight: yield 25.6 g (60%); white crystals; mp 95–97°C; Rf 0.38
Ph3P (115.5 g, 0.44 mol) was added to a stirred solution of C2Cl6
(104.3 g, 0.44 mol) in dry MeCN (1200 mL). The mixture was cooled to
0°C and treated with Et3N (89.0 g, 0.88 mol). The mixture was kept at
this temperature for 10 min, and a solution of aldehyde 9 (0.15 mol)
in dry MeCN (100 mL) was added in small portions, with the tem-
perature kept between 0 and 10°C. The resulting mixture was stirred
at room temperature for 14 h. The solvent was evaporated and the
residue was triturated with Et2O (400 mL). The precipitate was fil-
tered, washed with saturated aqueous NaHCO3 (to pHꢀ~ꢀ8) and then
with Et2O (2ꢀ×ꢀ200 mL). The organic layer was separated, washed with
brine (300 mL), dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography to give 11.
1
[CHCl3/MeOH (14:1)]; H NMR (CDCl3): δ 7.16 (br s, 0.6H) and 6.97
(s, 0.4H), 4.26–4.10 (m, 1H), 4.08–3.78 (m, 2H), 3.78–3.66 (m, 1H),
3.56–3.19 (m, 6H), 2.31–1.60 (m, 4H), 1.40 (s, 9H); 13C NMR (CDCl3):
δ 174.5 and 173.9, 155.5 and 154.7, 80.7, 70.8, 63.6, 61.1 and 60.3, 47.2,
42.0, 31.2, 29.3 and 28.3, 24.5 and 23.7. Anal. Calcd for C13H24N2O5:
C, 54.15; H, 8.39; N, 9.72. Found: C, 54.49; H, 8.62; N, 9.34. MS (CI):
+
289 (MH ).
General procedure for synthesis of aldehydes 9a–e
tert-Butyl (S)-2-(4-methyloxazol-2-yl) pyrrolidine-1-carboxylate
(11a)ꢁYield 22.1 g (60% for two steps); white solid; mp 55–57°C; Rf
0.45 [hexanes/EtOAc (1:1)]; [α]2D0 = −81.2 (c 0.50, MeOH); MS: m/z 275
(MNa ), 253 (MH ); H NMR (CDCl3): δ 7.26 (s, 1H), 4.96 (br s, 0.35H)
and 4.83 (br s, 0.65H), 3.67–3.55 (m, 1H), 3.54–3.39 (m, 1H), 2.35–2.18
(m, 1H), 2.14 (s, 3H), 2.12–1.99 (m, 2H), 1.97–1.84 (m, 1H), 1.45 (s, 3.2H)
and 1.29 (s, 5.8H); 13C NMR (CDCl3): δ 164.4, 153.8 and 153.4, 135.9, 133.4
and 132.9, 79.3, 54.6 and 54.2, 46.4 and 46.1, 32.2 and 31.2, 28.2 and
27.9, 24.0 and 23.4, 11.3. Anal. Calcd for C13H20N2O3: C, 61.88; H, 7.99; N,
11.1. Found: C, 61.87; H, 8.16; N, 11.45.
Method AꢁA suspension of alcohol 7 (0.12 mol) in CH2Cl2 (100 mL)
was added in small portions to a solution of the Dess-Martin reagent
(60.6 g, 0.14 mol) and t-BuOH (9.70 g, 0.13 mol) in CH2Cl2 (800 mL) at
0°C. Then the mixture was allowed to warm to room temperature,
and after the reaction was complete, as monitored by TLC, about 1 h,
the excess of the Dess-Martin reagent was neutralized with a solution
of Na2S2O3 (20 g) in saturated aqueous NaHCO3 (400 mL) with stirring.
After an additional 10 min of stirring, the mixture was transferred into
a separatory funnel. The organic phase was separated, washed with
brine (200 mL), dried over Na2SO4 and concentrated under reduced
pressure to give the crude product 9a–e which was immediately used
in the next step without purification. The temperature should be kept
below 20°C during all manipulations with the product, including the
evaporation of the solvent.
+
+
1
tert-Butyl (S)-2-(4-isopropyloxazol-2-yl) pyrrolidine-1-carbox-
ylate (11b)ꢁYield 61.4 g (70% for two steps); yellowish oil; Rf 0.41
[hexanes/EtOAc (4:1)]; [α]2D0 = –58.0 (c 0.50, MeOH); 1H NMR (CDCl3):
δ 7.22 (s, 1H), 4.97 (br s, 0.22H) and 4.84 (dd, Jꢀ=ꢀ8.0, 4.0 Hz, 0.78H),
3.69–3.55 (m, 1H), 3.55–3.34 (m, 1H), 2.81 (sept, Jꢀ=ꢀ6.7 Hz, 1H), 2.36–
2.14 (m, 1H), 2.14–1.97 (m, 2H), 1.96–1.84 (m, 1H), 1.45 (s, 2.3H) and
1.28 (s, 6.7H), 1.23 (d, Jꢀ=ꢀ6.8 Hz, 6H); 13C NMR (CDCl3): δ 164.2, 153.4,
146.8, 131.5 and 131.2, 79.2, 54.7 and 54.4, 46.1, 32.3 and 31.3, 28.1 and
27.9, 26.2, 24.0 and 23.4, 21.4 and 21.2. Anal. Calcd for C15H24N2O3: C,
64.26; H, 8.63; N, 9.99. Found: C, 64.27; H, 8.57; N, 10.36. MS: 281
Method BꢁA solution of DMSO (28.7 g, 0.37 mol) in CH2Cl2 (80 mL)
was added dropwise to a solution of oxalyl chloride (22.3 g, 0.18 mol)
in CH2Cl2 (1100 mL) at –60°C. The mixture was stirred for 20 min at
the same temperature and then treated with a suspension of alcohol
7 (0.15 mol) in CH2Cl2 (100 mL) at –60°C. The solution was stirred for
an additional 30 min at –60°C, then Et3N (79.9 g, 0.73 mol) was added
and the mixture was allowed to warm to 15°C. Water (250 mL) was
+
(MH ).
added, the mixture was stirred for 5 min and the organic phase was tert-Butyl (S)-2-(4-isobutyloxazol-2-yl)pyrrolidine-1-carboxy-
separated. The aqueous phase was washed with CH2Cl2 (150 mL). The late (11c)ꢁYield 44.8 g (63% for two steps); yellowish oil; Rf 0.35
combined organic extracts were dried over Na2SO4 and concentrated [hexanes/EtOAc (4:1)]; [α]2D0 = –60.6 (c 0.50, MeOH); MS: m/z 295
+
1
under reduced pressure to give the crude compound which was (MH ); H NMR (CDCl3): δ 7.25 (s, 1H), 4.95 (br s, 0.23H) and 4.83
immediately used in the next step without purification. The tempera- (dd, Jꢀ=ꢀ7.7, 3.6 Hz, 0.77H), 2.33 (d, Jꢀ=ꢀ7.3 Hz, 2H), 2.30–2.14 (m, 1H),
ture should be kept below 20°C during all manipulations with the 2.12–1.99 (m, 2H), 1.97–1.82 (m, 2H), 1.43 (s, 2.9H) and 1.28 (s, 6.1H),
product, including the evaporation of the solvent. For comparative 0.91 (d, Jꢀ=ꢀ6.6 Hz, 2H); 13C NMR (CDCl3): δ 164.2 and 164.0, 153.7 and
analysis of the methods A and B, see the main text.
153.4, 139.35, 133.6 and 133.3, 79.21, 54.6 and 54.3, 46.3 and 46.1,
35.1, 32.3 and 31.2, 28.1 and 27.9, 27.3, 24.0 and 23.4, 22.1. Anal. Calcd
for C16H26N2O3: C, 65.28; H, 8.90; N, 9.52. Found: C, 65.44; H, 8.56;
N, 9.31.
tert-Butyl (S)-2-[(2-oxoethyl)carbamoyl]pyrrolidine-
1-carboxylate (9e) (alternative procedure)
tert-Butyl (S)-2-(4-(tert-butyl)oxazol-2-yl)pyrrolidine-1-carboxy-
late (11d)ꢁYield 60.7 g (72% for two steps); beige solid; mp 66–67°C;
NaIO4 (37.2 g, 0.17 mol) was added in portions to a stirred solution Rf 0.43 [hexanes/EtOAc (4:1)]; [α]20 = –68.4 (c 0.50, MeOH); MS: m/z
D
of diol 7g (25.0 g, 0.087 mol) in tetrahydrofuran (THF) (250 mL) and 317 (MNa ), 295 (MH ); 1H NMR (CDCl3): δ 7.20 (s, 1H), 4.97 (br s, 0.13H)
H2O (250 mL) at 5–10°C. After stirring at 20°C for 1 h, the mixture was and 4.85 (dd, Jꢀ=ꢀ7.3, 3.6 Hz, 0.87H), 3.68–3.56 (m, 1H), 3.55–3.35 (m,
extracted with Et2O (4ꢀ×ꢀ150 mL) and the combined organic layers were 1H), 2.34–2.14 (m, 1H), 2.13–1.97 (m, 2H), 1.96–1.81 (m, 1H), 1.45 (s, 2H)
dried over Na2SO4 and concentrated under reduced pressure. The tem- and 1.27 (s, 7H), 1.24 (s, 9H); 13C NMR (CDCl3): δ 164.1, 153.4, 149.9,
perature should be kept below 20°C during all manipulations with the 130.4, 79.1, 54.8 and 54.4, 46.1, 32.2 and 31.4, 30.6, 29.0, 27.9, 23.9 and
product, including the evaporation of the solvent. The crude product 23.4. Anal. Calcd for C16H26N2O3: C, 65.28; H, 8.90; N, 9.52. Found: C,
+
+
9e was immediately used in the next step without purification.
65.62; H, 8.79; N, 9.24.
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ꢀꢀꢀꢁ
6ꢀ ꢀE.Y. Slobodyanyuk et al.: Proline-derived 2,4-disubstituted oxazoles
+
+
tert-Butyl
(S)-2-(oxazol-2-yl)pyrrolidine-1-carboxylate
(11e)ꢁ
δ 10.70 (br s, 1H, NHH ), 9.47 (br s, 1H, NHH ), 7.93 (s, 1H, 5-CH),
4.83–4.68 (m, 1H, 2′-CH), 3.32–3.19 (m, 2H, 5′-CH2), 2.42–2.30 (m, 1H,
3′-CHH), 2.24–2.12 (m, 1H, 3′-CHH), 2.10–1.90 (m, 2H, 4′-CH2), 1.21 (s,
9H, 3CH3); 13C NMR (DMSO-d6): δ 157.7 (2-C), 149.7 (4-C), 134.0 (5-C),
54.0 (2′-CH), 45.0 (5′-CH2), 30.6 (C(CH3)3), 29.1 (3CH3), 28.7 (3′-CH2),
23.5 (4′-CH2). Anal. Calcd for C11H20Cl2N2O: C, 49.45; H, 7.54; N, 10.48;
Cl, 26.54. Found: C, 49.25; H, 7.44; N, 10.42; Cl, 26.77.
Yield 25.0 g (35% for two steps); yellowish oil; Rf 0.52 [hexanes/
EtOAc (1:1)]; [α]2D0 = –54.0 (c 0.50, MeOH); MS: m/z 261 (MNa ), 139
+
+
(MH –C4H8–CO2); 1H NMR (CDCl3): δ 7.57 (s, 1H), 7.06 (s, 1H), 5.03 (br s,
0.35H) and 4.91 (dd, Jꢀ=ꢀ8.5, 3.5 Hz, 0.65H), 3.70–3.56 (m, 1H), 3.55–3.37
(m, 1H), 2.34–2.16 (m, 1H), 2.14–2.01 (m, 2H), 1.99–1.86 (m, 1H), 1.45 (s,
3H) and 1.28 (s, 6H); 13C NMR (CDCl3): δ 164.9 and 164.6, 153.3, 137.9
and 137.5, 126.4, 79.3, 54.5 and 54.1, 46.3 and 46.0, 32.1 and 31.0, 28.1
and 27.9, 23.9 and 23.3. Anal. Calcd for C12H18N2O3: C, 60.49; H, 7.61; N,
11.76. Found: C, 60.56; H, 7.73; N, 11.76.
(S)-2-(Pyrrolidin-2-yl)oxazole dihydrochloride (4eꢀ·ꢀ2HCl)ꢁYield
16.9 g (76%); beige solid; mp 167–169°C (dec.); [α]2D0 = –14.1 (c 0.50,
MeOH); MS: m/z 139 (MH ); H NMR (DMSO-d6): δ 10.71 (br s, 1H,
+
1
+
+
NHH ), 9.59 (br s, 1H, NHH ), 8.25 (d, Jꢀ=ꢀ0.8 Hz, 1H, 5-CH), 7.32 (d,
Jꢀ=ꢀ0.8 Hz, 1H, 4-CH), 4.90–4.76 (m, 1H, 2′-CH), 3.32–3.20 (m, 2H,
5-CH2), 2.43–2.31 (m, 1H, 3′-CHH), 2.22 (m, 1H, 3′-CHH), 2.12–1.91
(m, 2H, 4′-CH2); 13C NMR (DMSO-d6): δ 158.4 (2-C), 141.1 (5-CH), 127.2
(4-CH), 53.9 (2′-CH), 45.0 (5′-CH2), 28.7 (3′-CH2), 23.4 (4′-CH2). Anal.
Calcd for C7H12Cl2N2O: C, 39.83; H, 5.73; N, 13.27; Cl, 33.59. Found: C,
39.43; H, 5.85; N, 13.36; Cl, 33.53.
General procedure for synthesis of oxazoles 4a–eꢁ·ꢁ2HCl
A saturated solution of HCl in Et2O (ca. 24% w/w, 100 mL) was pre-
cooled to 5°C and added in portions to a solution of Boc derivative 11
(0.15 mol) in dry MeOH (200 mL) at room temperature. The mixture
was stirred vigorously at room temperature overnight, then concen-
trated (caution: violent gas emission) under reduced pressure and
the residue was triturated with Et2O (200 mL). The precipitate was
filtered and washed thoroughly with MeCN (80 mL) and dried under
reduced pressure to give the title product 4ꢀ·ꢀ2HCl.
Acknowledgments: This work was supported by Life
Chemicals Inc., Enamine Ltd. and Ukrainian Government
Funding (state registry no. 0114U003956). The authors
thank Prof. Andrey A. Tolmachev for his encouragement
and support, Mr. Andriy Kozitskiy for 2D NMR measure-
ments and Dr. Valeriya Makhankova for her help with
manuscript preparation.
(S)-4-Methyl-2-(pyrrolidin-2-yl)oxazole dihydrochloride (4aꢀ·ꢀ
2HCl)ꢁYield 26.5 g (77%); white solid; mp 126–128°C; [α]2D0 = –14.6
+
(c 0.50, MeOH); MS: m/z 153 (MH ); 1H NMR (DMSO-d6): δ 10.52 (br s,
+
+
1H, NHH ), 9.46 (br s, 1H, NHH ), 7.94 (q, Jꢀ=ꢀ1.3 Hz, 1H, 5-CH), 4.82–
4.74 (m, 1H, 2′-CH), 3.31–3.22 (m, 2H, 5′-CH2), 2.40–2.30 (m, 1H, 3′-
CHH), 2.23–2.14 (m, 1H, 3′-CHH), 2.11 (d, Jꢀ=ꢀ1.3 Hz, 3H, CH3), 2.08–1.92
(m, 2H, 4-CH2, 1H is exchangeable with D2O); 13C NMR (DMSO-d6): δ
158.0 (2-C), 136.4 (5-CH), 135.8 (4-C), 53.9 (2′-CH), 44.8 (5′-CH2), 28.6
(3′-CH2), 23.3 (4′-CH2), 11.1 (CH3). Anal. Calcd for C8H13Cl2N2O: C, 42.87;
H, 5.85; N, 12.50; Cl, 31.64. Found: C, 42.88; H, 5.49; N, 12.15; Cl, 31.98.
References
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(S)-4-Isopropyl-2-(pyrrolidin-2-yl)oxazole dihydrochloride (4bꢀ·ꢀ
2HCl)ꢁYield 43.1 g (80%); white solid; mp 134–136°C; [α]2D0 = –13.2 (c
+
0.50, MeOH); MS: m/z 181 (MH ); 1H NMR (DMSO-d6): δ 10.71 (br s, 1H,
+
+
NHH ), 9.49 (br s, 1H, NHH ), 7.94 (d, Jꢀ=ꢀ1.2 Hz, 1H, 5-CH), 4.82–4.71 (m,
1H, 2′-CH), 3.31–3.21 (m, 2H, 5′-CH2), 2.78 (m, 1H, CH(CH3)2), 2.42–2.30
(m, 1H, 3′-CHH), 2.24–2.12 (m, 1H, 3′-CHH), 2.11–1.93 (m, 2H, 4′-CH2), 1.18
(d, Jꢀ=ꢀ6.9 Hz, 6H, 2CH3); 13C NMR (DMSO-d6): δ 158.0 (2-C), 146.6 (4-C),
134.9 (5-CH), 54.0 (2′-CH), 44.9 (5′-CH2), 28.6 (3′-CH2), 25.7 (CH(CH3)2),
23.3 (3′-CH2), 21.3 (2CH3). Anal. Calcd for C10H18Cl2N2O: C, 47.44; H, 7.17;
N, 11.07; Cl, 28.01. Found: C, 47.5; H, 6.90; N, 11.11; Cl, 28.23.
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(S)-4-Isobutyl-2-(pyrrolidin-2-yl)oxazole dihydrochloride (4cꢀ·ꢀ
2HCl)ꢁYield 45.0 g (82%); white solid; mp 108–111°C; [α]2D0 = –12.4 [6] Wales, S. M.; Hammer, K. A.; Somphol, K.; Kemker, I.; Schröder,
+
1
(c 0.50, MeOH); MS: m/z 195 (MH ); H NMR (DMSO-d6): δ 10.59 (br
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+
+
s, 1H, NHH ), 9.47 (br s, 1H, NHH ), 7.95 (s, 1H, 5-CH), 4.84–4.74 (m,
1H, 2′-CH), 3.31–3.22 (m, 2H, 5′-CH2), 2.43–2.35 (m, 1H, 3′-CHH), 2.34 (d,
Jꢀ=ꢀ6.9 Hz, 2H, CH2CH(CH3)2), 2.24–2.12 (m, 1H, 3′-CHH), 2.11–1.94 (m, 2H,
4′-CH2), 1.94–1.81 (m, 1H, CH2CH(CH3)2), 0.90 (d, Jꢀ=ꢀ6.6 Hz, 6H, 2CH3); [7] Murru, S.; Nefzi, A. Combinatorial synthesis of oxazol-thiazole
13C NMR (DMSO-d6): δ 157.9 (2-C), 139.3 (4-C), 136.7 (5-CH), 53.9 (2′-CH),
bis-heterocyclic compounds. ACS Comb. Sci. 2014, 16, 39–45.
44.9 (5′-CH2), 34.4 (CH2CH(CH3)2), 28.6 (3′-CH2), 27.1 (CH2CH(CH3)2), 23.3 [8] Blankson, G. A.; Pilch, D. S.; Liu, A. A.; Liu, L. F.; Rice, J. E.;
(4′-CH2), 22.1 (2CH3). Anal. Calcd for C11H20Cl2N2O: C, 49.45; H, 7.54; N,
10.48; Cl, 26.54. Found: C, 49.13; H, 7.49; N, 10.71; Cl, 26.47.
Lavoie, E. J. Macrocyclic biphenyl tetraoxazoles: synthesis,
evaluation as G-quadruplex stabilizers and cytotoxic activity.
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(S)-4-(tert-Butyl)-2-(pyrrolidin-2-yl)oxazole
dihydrochloride
[9] Murru, S.; Dooley, C. T.; Nefzi, A. Parallel synthesis of
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(4dꢀ·ꢀ2HCl)ꢁYield 38.2 g (85%); white solid; mp 141–142°C (dec.);
[α]2D0 = –13.4
(c 0.50, MeOH); MS: m/z 195 (MH ); 1H NMR (DMSO-d6):
+
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ꢁꢀꢀꢀ
ꢂ7
E.Y. Slobodyanyuk et al.: Proline-derived 2,4-disubstituted oxazolesꢂ
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