Stereoselective synthesis of oxazolidin-2-ones via an asymmetric aldol/curtius reaction: Concise total synthesis of (?)-cytoxazone

Article abstract of DOI:10.3390/molecules26030597

Herein, we are reporting an efficient approach toward the synthesis of 4,5-disubstituted oxazolidin-2-one scaffolds. The developed approach is based on a combination of an asymmetric aldol and a modified Curtius protocol, which uses an effective intramolecular ring closure to rapidly access a range of oxazolidin-2-one building blocks. This strategy also permits a straightforward and concise asymmetric total synthesis of (?)-cytoxazone. Consisting of three steps, this is one of the shortest syntheses reported to date. Ultimately, this convenient platform would provide a promising method for the early phases of drug discovery.

Full text of DOI:10.3390/molecules26030597

molecules
Article
Stereoselective Synthesis of Oxazolidin-2-ones via an
Asymmetric Aldol/Curtius Reaction: Concise Total Synthesis
of (−)-Cytoxazone
Hosam Choi, Hanho Jang, Joohee Choi and Kiyoun Lee *
Department of Chemistry, The Catholic University of Korea, Bucheon 14662, Korea; pzpz1233@gmail.com (H.C.);
gksghwkd0925@gmail.com (H.J.); cholo4015@naver.com (J.C.)
*
Correspondence: kiyoun@catholic.ac.kr; Tel.: +82-2-2164-5528; Fax: +82-2-2164-4764
Abstract: Herein, we are reporting an efficient approach toward the synthesis of 4,5-disubstituted
oxazolidin-2-one scaffolds. The developed approach is based on a combination of an asymmetric
aldol and a modified Curtius protocol, which uses an effective intramolecular ring closure to rapidly
access a range of oxazolidin-2-one building blocks. This strategy also permits a straightforward and
concise asymmetric total synthesis of ( )-cytoxazone. Consisting of three steps, this is one of the
−
shortest syntheses reported to date. Ultimately, this convenient platform would provide a promising
method for the early phases of drug discovery.
Keywords: oxazolidin-2-one; ( )-cytoxazone; natural product; total synthesis; curtius reaction;
−
asymmetric aldol
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
1
. Introduction
Citation: Choi, H.; Jang, H.; Choi, J.;
Lee, K. Stereoselective Synthesis of
Oxazolidin-2-ones via an Asymmetric
Aldol/Curtius Reaction: Concise
Total Synthesis of (−)-Cytoxazone.
Molecules 2021, 26, 597. https://
doi.org/10.3390/molecules26030597
Functionalized oxazolidin-2-ones are among the most interesting heterocyclic com-
pounds, with uses both as pharmaceuticals and as key synthetic intermediates
(Scheme 1a). Since the seminal discovery of anti-bacterial activity of certain oxazolidin-
2-ones by EI DuPont de Nemours and Co., Inc. in 1987 [
oxazolidin-2-one motifs has drawn a considerable amount of interest from the synthetic
community [ ]. These functionalized oxazolidin-2-one compounds have demonstrated
a wide spectrum of pharmacological properties [ ]. For instance, linezolid (LZD), the
first synthetic oxazolidin-2-one antimicrobial agent, has shown potent efficacy against
Gram-positive bacteria through the inhibition of bacterial protein synthesis [ ]. LZD was
approved by the FDA for the treatment of a range of traditionally drug-resistant infections,
including MRSA and drug-resistant tuberculosis in 2002 [ ]. Tedizolid is also a promising
1], the synthesis of substituted
2,3
4–6
Academic Editor: Francesca Marini
Received: 13 January 2021
7,8
Accepted: 21 January 2021
Published: 23 January 2021
9
antibacterial agent that is used to treat skin infection in adults [10]. Thanks for these
pharmacological properties, structurally diverse oxazolidin-2-one motifs often serve as key
synthetic intermediates within the context of macrolide antibiotics syntheses. Additionally,
these cyclic carbamate moieties are one of the most significant and widely utilized chiral
auxiliaries in the realm of organic synthesis [11–13].
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Due to the amount of intrigue surrounding the unique structural features and diverse
therapeutic utility, in the past decades, great emphasis has been placed on the develop-
ment of synthetic approaches toward the enantioselective construction of oxazolidin-2-one
moieties. There are several conventional approaches for the construction of oxazolidin-2-
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Licensee MDPI, Basel, Switzerland.
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ones. One of the most common methods involves the intermolecular reaction of a
alcohol with phosgene (Scheme 1b) [14,15].
β-amino
4
.0/).
Molecules 2021, 26, 597. https://doi.org/10.3390/molecules26030597
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 597
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−
Scheme 1.
(a
) Natural products and pharmaceuticals containing oxazolidin-2-ones (
b) Conventional
method towards the oxazolidin-2-ones (c) Proposed Strategy for the synthesis of the 4,5-disubstituted
oxazolin-2-one framework.
However, these types of method suffer from limited availability of starting materials,
in some cases, due to the need for a pre-installed stereogenic center on the -amino alcohol
prior to ring closure. Alternative common strategies include the reaction of isocyanates
with epoxides and the reaction of aziridines with carbon dioxide [16 18]. Despite these
β
–
advances in the field of oxazolidin-2-one synthesis, successful methods are thus far largely
limited in terms of the access to substrates, regio- and stereochemical outcome, ability
to increase molecular complexity of easily obtainable starting materials, and sufficiently
mild reaction conditions that are compatible with various functional groups. Furthermore,
to date, the asymmetric synthesis of oxazolidin-2-one motifs has thus far remained out
of reach. More specifically, many asymmetric strategies reported to have focused on the
generation of C4- or C5-monosubstituted oxazolidinones, while strategies providing access
to oxazolidinones possessing 4,5-two vicinal stereogenic centers have rarely been reported.

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These aspects have resulted in the continuous demand for new synthetic approaches for
the construction of optically active oxazolidin-2-one moieties.
To meet this synthetic need, herein we disclose studies on the development of an effi-
cient synthesis of oxazolidin-2-one scaffolds with access to 4,5-vicinal stereogenic centers,
which uses a combination of an asymmetric aldol and a modified Curtius procedure to
undergo an effective intramolecular cyclization. This convenient platform consequently
permitted the concise total synthesis of natural (
the best of our knowledge, this work presents the shortest asymmetric total synthesis of
−
)-cytoxazone (1) in only three steps. To
(
−)-cytoxazone reported to date.
The Curtius approach most commonly involves the isolation of acyl azides from
carboxylic acid derivatives such as acyl chlorides or mixed anhydrides [19–21]. However,
the acid chloride itself often raises the issue of compatibility with acid-labile functionalities
and has additional drawbacks such as issues with preparation and storage. Alternative
one-pot protocols for the synthesis of carbarmates from carboxylic acids by employing
the diphenylphosphoryl azide (DPPA) have been more attractive [22,23]. Though quite
efficient, toxicity issues and purification difficulties have been inescapable, resulting in
restriction of scope and consequently, synthetic utility.
2. Results and Discussion
Keeping these considerations in mind, we were interested in the direct conversion of
chiral imides to cyclic carbamates without the isolation of highly reactive acyl chlorides
and/or unstable acyl azides. As illustrated in Scheme 1c, we envisaged that efficient,
direct, and even diastereoselective construction of an optically active 4,5-disubstituted
oxazolidin-2-one motif would be possible if a chiral auxiliary-mediated asymmetric aldol
reaction was utilized in conjunction with the Curtius rearrangement, followed by in situ
intramolecular ring closure in a tandem manner.
In terms of the simplified reaction mechanism, upon treatment with sufficiently
nucleophilic azide transfer reagents, the chiral auxiliary bearing starting material
I could be
converted into acyl azide intermediate II. Subsequent thermal decomposition results in the
formation of an acyl nitrene with the loss of N , followed by the molecular rearrangement
2
to generate the desired chiral oxazolidin-2-one, presumably through the intramolecular
ring closure of the isocyanate intermediate III.
In order to test this hypothesis, syn-aldol adduct 3a was prepared as a model substrate
by employing an Evans type auxiliary-mediated aldol protocol [11
procedure described by Crimmins [27 29] (Scheme 2). Initially, we attempted the direct
nucleophilic azidation/Curtius reaction by treatment of 3a with Bu SnN (3 equiv., THF,
,24–26] following the
–
3
3
◦
9
0 C). To our disappointment, the reaction only produced a trace amount (less than 2%) of
product (entry 1). Introducing an oxazolidinethione in syn-aldol product 3b and ensuing
4
subjection in the nucleophilic azide transfer/Curtius reaction improved the yield, but only
to 13% (entry 2).
These low conversions could be attributed to the inherent electrophilic nature of C1 car-
bonyl carbon in 3a–c and the associated inhibition of the initial acyl azide formation. There-
fore, we envisioned that corresponding aldol precursors with diminished electrophilicity
at C1 in auxiliaries would potentially be more productive than oxazolidinones or oxazo-
lidinethiones in establishing more effective construction of the oxazolidin-2-ones [29,30].
Consistent with our expectation, the nucleophilic azidation/Curtius reaction of thiazo-
◦
lidinethione 3c under the same reaction conditions (Bu SnN , THF, 90 C) proceeded to
3
3
provide corresponding oxazolidin-2-one 4 in higher conversion (57%).

Molecules 2021, 26, 597
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−
a
Scheme 2. Synthesis of oxazolidin-2-one via the azidation/Curtius rearrangement sequence. Iso-
b
lated yield of major diastereomer. Reaction conditions: 0.05–0.2 mmol of 3a
–
c
. Bu SnN (3 equiv.,
3
3
3
0 min, entries 1–3), Me AlN (3 equiv., 5 min, entries 4–6), Me SiN (3 equiv., 3–5 h, entries 7–12),
2 3 3 3
c
(
n-Bu) NN (3 equiv., 2 h, entries 13–15), NaN (10 equiv., 5 h, entries 16–18). Commercially
4
3
3
available. d Isolated yield. e No reaction was observed.
Encouraged by this promising result, we contemplated a series of alternative chiral
auxiliaries and several N transfer reagents and ultimately found that a combination of
3
the use of asymmetric syn-aldol products bearing N-acylthiazolidinethione with a Bn or
◦
an i-Pr moiety and treatment with Me SiN [31] (3 equiv., THF, 90 C, entry 9) proved to
3
3
be highly effective and cleanly afforded the corresponding oxazolidin-2-one 4 in superb
conversion (89%). Optimization of the solvent system revealed that THF was the best
solvent of those examined (entries 9–12). The use of higher reaction concentrations (0.2 M)
or prolonged reaction times (12 h) did not further improve the already excellent yield.
It is worth mentioning that the developed protocol proceeds with complete retention of
the enantiomeric excess and the diastereoselectivity in
4 (see Supplementary Material).
Alternative nucleophilic azide transfer reactions (M Al-N /THF or (n-Bu) NN /THF)
2
3
4
3
were also successful, but afforded
4 in lower conversions (Scheme 2, entries 4–6, 13–15).

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However, reactions that employed NaN proved ineffective in all tested solvent systems
3
(
DMF, MeCN, and acetone) (entries 16–18).
To gain further insight into the effect of thiazolidinethione moiety in compound 3c, we
next sought to address the reactivity with
a
simpler ester functionality
(
(
Scheme 3). To this end, methyl ester
20 mol%), MeOH (1.5 equiv.), CH Cl , 25 C) and subsequent azidation/Curtius reaction
5 was prepared by methanolysis of 3c (DMAP
◦
2
2
in the presence of Me AlN gave the oxazolidin-2-one
4
in low yield (23%). Surprisingly, the
2
3
azidation/Curtius reactions of
failed to provide the corresponding
and significant decomposition for the latter two cases. Subsequently, carboxylic acid
was also evaluated by the treatment of DPPA (Et N, benzene, reflux), which proceeded
5 with the treatment of Me SiN , Bu SnN , or (n-Bu) NN
3
3
3
3
4
3
4, but rather only resulted in no reactivity for the former
6
3
to provide
4 in 84%, suggesting that a direct mode of oxazolidin-2-one formation from a
substrate such as 3c may constitute a more effective approach than a multi-step process.
Scheme 3. Synthesis of 4,5-disubstituted oxazolidin-2-ones from
5 and 6
. a Isolated yield. b No
reaction was observed. DPPA = diphenyl phosphoryl azide.
Having achieved optimal reaction conditions, we set out to explore the scope and
the limitations of this transformation (Scheme 4). A series of -hydroxy carbonyl sub-
β
strates bearing aryl and aliphatic substituents were synthesized and found to react well
to afford the desired 4,5-disubstituted oxazolidin-2-ones in good to excellent conversions.
Electron-neutral and electron-rich aryl motifs, such as p-chlorophenyl (7a), p-fluorophenyl
(
7b), p-methoxyphenyl (7e), and thiophene (7c) groups, readily proceeded to provide the
desired products 8a and 8e (90–97%). Substrates with strong electron withdrawing func-
tionalities, such as p-cyano (7h), p-nitro (7i), and p-trifluoromethyl (7j) were also tolerated
to generate the corresponding oxazolidin-2-ones (8h 8j, 79–80%). In addition, expanding
–c
–
the scope to aliphatic substituents (7k and 7l) proved to be feasible and provided the
corresponding products 8k and 8l (73–90%), demonstrating excellent compatibility with a
range of functional groups.
To demonstrate the synthetic utility of the present methodology, we tackled the
synthesis (
−
)-cytoxazone (
1
). ( )-Cytoxazone was originally isolated from cultures of
−
Streptomyces sp. in 1998 by Osada and co-workers [32]. Structural elucidation and relative
stereochemistry was established by a combination of high-resolution mass spectroscopy
and two-dimensional-NMR studies, while the absolute configuration was secured via the
comparison of CD spectra with authentic samples, as well as the enantioselective synthesis
by Nakata and co-workers [33]. It was reported that ( )-cytoxazone exhibited a cytokine
−
modulator effect via the signaling pathway of Th2 cells (type 2 cytokines), which is involved
in cell growth and differentiation [34]. These interesting pharmacological properties made

Molecules 2021, 26, 597
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this natural product and its analogs important targets for chemical synthesis, resulting in
more than thirty to date [35–39].
a
a
Scheme 4. Substrate scope of the synthesis of 4,5-disubstituted oxazolidin-2-ones . All reactions
b
were run on 0.1–0.2 mmol scale under the standard conditions. Yields of isolated products after
purification by flash chromatography.
Our synthesis of (
addition of chlorotitanium enolate of
−
)-cytoxazone (
1
) is illustrated in Scheme 5. An asymmetric aldol
9
upon treatment with 2-benzyloxyacetaldehyde 10
furnished the syn-aldol adduct 11 in 98% yield (dr 3:1). Subsequent nucleophilic azida-
tion/Curtius reaction of the resulting 11 in the presence of trimethylsilyl azide (3 equiv.,
◦
THF, 90 C, 5 h) smoothly proceeded to afford the desired cyclic carbamate 12 in 87%
yield as a single diastereomer. Attempts with other methods (Bu SnN or (n-Bu) NN ,
3
3
4
3
◦
3
equiv., THF, 90 C) were also successful but afforded 12 in lower conversions (11–17%).
Lastly, removal of benzyl group (Pd/C, H , EtOH) allowed the completion of the synthesis
2
of (
−
)-cytoxazone (1), whose properties proved identical in all respects with those of an
authentic sample of the natural product.

Molecules 2021, 26, 597
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−
−
Scheme 5. Concise total synthesis of (
non-Evans syn = 3:1) was observed.
−
)-cytoxazone (
1
). a A mixture of diastereomers (Evans syn:
3. Experimental Section
3.1. General Information
All reactions were conducted in oven-dried glassware under nitrogen. Unless oth-
erwise stated, all reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA),
Acros, or Fisher (Hampton, NH, USA), and were used without further purification. All
solvents were ACS grade or better and used without further purification. Analytical thin
layer chromatography (TLC) was performed with glass backed silica gel (60 Å) plates with
fluorescent indication (Whatman, St. Louis, MO, USA). Visualization was accomplished
by UV irradiation at 254 nm and/or by staining with ninhydrin, phosphomolybdic acid
(
PMA) solution, or p-anisaldehyde solution. Flash column chromatography was performed
1
13
by using silica gel (particle size 70–230 mesh ASTM). All H-NMR and C-NMR spectra
were recorded at 298 K on a Bruker Avance III HD 500 MHz (Bruker Corporation, Billerica,
MA, USA) spectrometer in CDCl by using the signal of residual CHCl , as an internal
3
3
standard. All-NMR δ values are given in ppm, and all J values are in Hz. Optical rotation
values were measured with a Rudolph Research Analytical (AUTOPOL II, Hackettstown,
NJ, USA) polarimeter.
3
.2. Representative Procedure for the Synthesis of 4
4S,5R)-4-methyl-5-phenyloxazolidin-2-one ( ): A solution of (2S,3S)-3-hydroxy-1-((S)-4-
isopropyl-2-thioxothiazolidin-3-yl)-2-methyl-3-phenylpropan-1-one 3c (38.9 mg, 0.120 mmol,
(
4
1
.0 equiv.) in THF (1.2 mL, 0.1 M) was treated with Me SiN (47.0
µ
L, 0.360 mmol, 3.0 equiv.)
3
3
◦
◦
and the resulting mixture was heated to reflux at 90 C. After stirring for 5 h at 90 C,
the resulting mixture was cooled to 25 C, quenched with the addition of H O, and di-
◦
2
luted with CH Cl . The layers were separated, and the aqueous layer was extracted with
2
2
CH Cl . The combined organic layers were washed with saturated aqueous NaCl, dried
2
2
over anhydrous Na SO , and concentrated in vacuo. The residue was purified by column
2
4
chromatography (SiO , gradient eluent: 25–75% EtOAc/hexane) to provide (4S,5R)-4-
2
25
methyl-5-phenyloxazolidin-2-one
CHCl ); H-NMR (500 MHz, CDCl )
4
(19.0 mg, 89%) as a white powder: [
δ 7.35–7.40 (m, 2H), 7.31–7.34 (m, 1H), 7.27–7.29 (m,
3
α]D –165 (c 0.60,
1
3
2
H), 6.79 (br s, 1H), 5.70 (d, J = 8.1 Hz, 1H), 4.18–4.24 (m, 1H), 0.80 (d, J = 6.6 Hz, 3H);

Molecules 2021, 26, 597
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13C-NMR (125 MHz, CDCl3)
δ
159.8, 134.9, 128.4, 128.3, 125.8, 80.9, 52.3, 17.4; HRMS
+
(
Q–TOF) m/z 178.0874 [(M + H) , C H NO requires 178.0868].
10 12 2
3.3. Synthesis of Oxazolidin-2-one (8a–8l)
A solution of 7a 7l (1.0 equiv.) in THF (0.1 M) was treated with Me SiN (3.0 equiv.)
–
3
3
◦
◦
and the resulting mixture was heated to reflux at 90 C. After stirring for 5 h at 90 C, the
resulting mixture was cooled to 25 C, quenched with the addition of H O, and diluted with
◦
2
CH Cl . The layers were separated, and the aqueous layer was extracted with CH Cl . The
2
2
2
2
combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous
Na SO , and concentrated in vacuo. The residue was purified by column chromatography
2
4
(
SiO , gradient eluent: 25–75% EtOAc/hexane) to provide 8a–8l.
2
(
4S,5R)-5-(4-chlorophenyl)-4-methyloxazolidin-2-one (8a): A white solid: [
α
]D25 –124 (c 0.72,
1
CHCl ); H-NMR (500 MHz, CDCl )
(
(
2
δ
7.37 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.32
3
3
1
3
br s, 1H), 5.68 (d, J = 8.0 Hz, 1H), 4.17–4.23 (m, 1H), 0.81 (d, J = 6.5 Hz, 3H); C-NMR
125 MHz, CDCl3) 159.3, 134.4, 133.4, 128.8, 127.3, 80.3, 52.2, 17.5; HRMS (Q–TOF) m/z
δ
+
12.0484 [(M + H) , C H ClNO requires 212.0478].
10 11 2
(
4S,5R)-5-(4-fluorophenyl)-4-methyloxazolidin-2-one (8b): A white solid: [
α
]D25 –104 (c 0.27,
1
CHCl ); H-NMR (500 MHz, CDCl )
(
(
δ
7.26–7.30 (m, 2H), 7.09 (td, J = 8.7, 2.5 Hz, 2H), 5.87
3
3
1
3
br s, 1H), 5.70 (d, J = 7.9 Hz, 1H), 4.17–4.23 (m, 1H), 0.81 (d, J = 6.5 Hz, 3H); C-NMR
125 MHz, CDCl3)
δ
162.7 (d, J = 245.8 Hz), 159.1, 130.6 (d, J = 3.2 Hz), 127.7 (d, J = 8.2 Hz),
+
1
15.6 (d, J = 21.6 Hz), 80.4, 52.3, 17.5; HRMS (Q–TOF) m/z 196.0779 [(M + H) , C H FNO
1
0
11
2
requires 196.0774].
(
4S,5R)-4-methyl-5-(thiophen-2-yl)oxazolidin-2-one (8c): A white oil: [
α
]D25 –33.3 (c 0.09,
1
CHCl ); H-NMR (500 MHz, CDCl )
(
(
δ
7.34 (dd, J = 4.9, 1.3 Hz, 1H), 7.02–7.07 (m, 2H), 5.92
3
3
1
3
d, J = 7.8 Hz, 1H), 5.57 (br s, 1H), 4.17–4.24 (m, 1H), 1.00 (d, J = 6.5 Hz, 3H); C-NMR
125 MHz, CDCl3)
84.0439 [(M + H) , C H NO S requires 184.0432].
δ
158.5, 137.1, 126.9, 126.1, 125.9, 78.2, 52.6, 17.0; HRMS (Q–TOF) m/z
+
1
8
10
2
(
–
4S,5R)-5-(4-(benzyloxy)-3-methoxyphenyl)-4-methyloxazolidin-2-one (8d): A white oil: [
α
]D25
1
50.0 (c 0.20, CHCl ); H-NMR (500 MHz, CDCl )
δ
7.43 (d, J = 7.2 Hz, 2H), 7.35–7.39 (m,
3
3
2
H), 7.29–7.33 (m, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 1.9 Hz, 1H), 6.74 (dd, J = 8.3,
1
(
.9 Hz, 1H), 5.65 (d, J = 7.9 Hz, 1H), 5.44 (br s, 1H), 5.16 (s, 2H), 4.11–4.17 (m, 1H), 3.90
s, 3H), 0.83 (d, J = 6.5 Hz, 3H); 13C-NMR (125 MHz, CDCl3)
δ 159.0, 149.7, 148.2, 136.8,
1
3
28.6, 127.9, 127.7, 127.3, 118.4, 113.7, 109.4, 80.9, 71.0, 56.1, 52.5, 17.5; HRMS (Q–TOF) m/z
+
14.1393 [(M + H) , C H NO requires 314.1392].
18
20
4
(
4S,5R)-5-(4-methoxyphenyl)-4-methyloxazolidin-2-one (8e): A white solid: [
α
]D25 –87.4 (c 0.24,
1
CHCl ); H-NMR (500 MHz, CDCl )
δ
7.21 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 5.79
3
3
(
br s, 1H), 5.67 (d, J = 7.9 Hz, 1H), 4.13–4.20 (m, 1H), 3.82 (s, 3H), 0.82 (d, J = 6.5 Hz, 3H);
13
C-NMR (125 MHz, CDCl3)
δ
159.7, 159.4, 127.3, 126.8, 113.9, 80.9, 55.3, 52.5, 17.5; HRMS
+
(
Q–TOF) m/z 208.0980 [(M + H) , C H NO requires 208.0974].
11
14
3
(
[
4S,5R)-5-(7-methoxybenzo[d][1,3]dioxol-5-yl)-4-methyloxazolidin-2-one (8f): A colorless oil:
25
1
α]D –122 (c 0.24, CHCl ); H-NMR (500 MHz, CDCl ) δ 6.48 (d, J = 1.1 Hz, 1H), 6.45 (d,
3
3
J = 1.1 Hz, 1H), 5.99 (s, 2H), 5.82 (br s, 1H), 6.11 (d, J = 7.9 Hz, 1H), 4.11–4.17 (m, 1H), 3.90
(
1
s, 3H), 0.86 (d, J = 6.5 Hz, 3H); 13C-NMR (125 MHz, CDCl3)
29.2, 105.5, 101.7, 100.2, 80.8, 56.7, 52.5, 17.4; HRMS (Q–TOF) m/z 252.0876 [(M + H) ,
δ
159.1, 149.1, 143.7, 135.2,
+
C H NO requires 252.0872].
12
14
5
(
(
1
4S,5R)-4-methyl-5-(3,4,5-trimethoxyphenyl)oxazolidin-2-one (8g): A colorless oil: [
α
]D25 –53.8
1
c 0.39, CHCl ); H-NMR (500 MHz, CDCl )
δ
6.49 (s, 2H), 5.86 (br s, 1H), 5.65 (d, J = 7.9 Hz,
3
3
13
H), 4.13–4.19 (m, 1H), 3.86 (s, 6H), 3.85 (s, 3H), 0.86 (d, J = 6.5 Hz, 3H); C-NMR (125 MHz,
CDCl3)
δ
159.2, 153.4, 137.8, 130.3, 102.8, 80.9, 60.9, 56.2, 52.5, 17.4; HRMS (Q–TOF) m/z
+
268.1186 [(M + H) , C H NO requires 268.1185].
13
18
5

Molecules 2021, 26, 597
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4
-((4S,5R)-4-methyl-2-oxooxazolidin-5-yl)benzonitrile (8h): A white solid: [
α
]D25 –160 (c 0.05,
1
CHCl ); H-NMR (500 MHz, CDCl )
δ
7.72 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 5.75
3
3
1
3
(
(
d, J = 7.9 Hz, 1H), 5.61 (br s, 1H), 4.23–4.29 (m, 1H), 0.81 (d, J = 6.5 Hz, 3H); C-NMR
125 MHz, CDCl3)
δ
158.3, 140.1, 132.4, 126.7, 118.2, 112.6, 79.9, 52.0, 17.6; HRMS (Q–TOF)
+
m/z 203.0829 [(M + H) , C H N O requires 203.0821].
11
11
2
2
(
4S,5R)-4-methyl-5-(4-nitrophenyl)oxazolidin-2-one (8i): A white solid: [
α
]D25 –225 (c 0.04,
1
CHCl ); H-NMR (500 MHz, CDCl )
5
δ
8.27 (dd, J = 7.0, 1.8 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H),
3
3
1
3
.81 (d, J = 8.0 Hz, 1H), 5.68 (br s, 1H), 4.26–4.33 (m, 1H), 0.83 (d, J = 6.5 Hz, 3H); C-NMR
(
2
125 MHz, CDCl3) 158.3, 148.1, 142.0, 126.9, 123.9, 79.7, 52.0, 17.7; HRMS (Q–TOF) m/z
δ
+
23.0723 [(M + H) , C H N O requires 223.0719].
10 11 2 4
(
(
5
4S,5R)-4-methyl-5-(4-(trifluoromethyl)phenyl)oxazolidin-2-one (8j): A white solid: [
α
]D25 –72.3
1
c 0.65, CHCl ); H-NMR (500 MHz, CDCl )
δ
7.67 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H),
3
3
1
3
.91 (br s, 1H), 5.77 (d, J = 7.7 Hz, 1H), 4.23–4.29 (m, 1H), 0.82 (d, J = 6.5 Hz, 3H); C-NMR
(
125 MHz, CDCl3)
δ
158.9, 138.9, 130.8 (q, J = 32.5 Hz), 126.3, 125.6 (q, J = 3.8 Hz), 123.8
+
(q, J = 270.6 Hz), 80.1, 52.1, 17.6; HRMS (Q–TOF) m/z 246.0744 [(M + H) , C H F NO
11
11
3
2
requires 246.0742].
(
4S,5R)-5-heptyl-4-methyloxazolidin-2-one (8k): A colorless oil: [
α
]D25 +12.6 (c 0.34, CHCl3);
6.06 (br s, 1H), 4.52–4.57 (m, 1H), 3.85–3.92 (m, 1H), 1.68–1.76
m, 1H), 1.46–1.52 (m, 2H), 1.26–1.33 (m, 9H), 1.14 (d, J = 6.5 Hz, 3H), 0.87 (t, J = 6.9 Hz,
1
H-NMR (500 MHz, CDCl3)
δ
(
3
1
1
3
H); C-NMR (125 MHz, CDCl3)
δ
159.8, 80.2, 51.1, 31.7, 29.3, 29.10, 29.05, 25.8, 22.6, 15.9,
+
4.0; HRMS (Q–TOF) m/z 208.1314 [(M+Na) , C H NNaO requires 208.1313].
10
19
2
(
4S,5R)-5-butyl-4-methyloxazolidin-2-one (8l): A colorless oil: [
α
]D25 +14.8 (c 0.27, CHCl3);
5.70 (br s, 1H), 4.53–4.58 (m, 1H), 3.86–3.92 (m, 1H), 1.70–1.77
m, 1H), 1.48–1.56 (m, 2H), 1.31–1.41 (m, 3H), 1.16 (d, J = 6.5 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H);
1
H-NMR (500 MHz, CDCl3)
δ
(
1
3
C-NMR (125 MHz, CDCl )
δ
159.6, 80.2, 51.1, 28.8, 27.9, 22.4, 15.9, 13.9; HRMS (Q–TOF)
3
+
m/z 144.1032 [(M + H) , C H NO requires 144.1025].
7
14
2
3.4. Synthesis of (–)-Cytoxazone
(
2R,3R)-1-((R)-4-benzyl-2-thioxothiazolidin-3-yl)-4-(benzyloxy)-3-hydroxy-2-(4-
◦
methoxyphenyl)butan-1-one (11): A cooled (0 C) solution of (R)-1-(4-benzyl-2-
thioxothiazolidin-3-yl)-2-(4-methoxyphenyl)ethan-1-one
9 (118 mg, 0.330 mmol, 1.0 equiv.)
in CH Cl (3.3 mL, 0.1 M) was treated with titanium(IV) chloride (0.36 mL, 1.0 M in CH Cl ,
2
2
2
2
◦
0
.36 mmol, 1.1 equiv.). After stirring for 30 min at 0 C, i-Pr NEt (0.14 mL, 0.83 mmol, 2.5
equiv.) was added dropwise and the resulting mixture was stirred for 2 h at 0 C. 1-methyl-
2
◦
2
-pyrrolidinone (NMP, 64
µ
L, 0.66 mmol, 2.0 equiv.) was added, and the resulting mixture
◦
was stirred for an additional 1 h and then cooled to
10 (148 mg, 0.990 mmol, 3 equiv.) in CH Cl (2 mL) was added to the above enolate,
−
20 C. 2-(benzyloxy)acetaldehyde
2 2
and the resulting mixture was stirred for 1 h before it was quenched with the addition of
saturated aqueous NH Cl, and diluted with CH Cl . The layers were separated, and the
4
2
2
aqueous layer was extracted with CH Cl . The combined organic layers were washed with
2
2
saturated aqueous NaCl, dried over anhydrous Na SO , and concentrated in vacuo. The
2
4
residue was purified by column chromatography (SiO , 20% EtOAc/hexane) to provide an
2
Evans syn aldol adduct 11 (124 mg, 74%) and a non-Evans syn aldol adduct (40 mg, 24%)
25
1
as yellow oils: For 11: [
m, 2H), 7.28–7.36 (m, 6H), 7.23–7.27 (m, 2H), 7.18–7.21 (m, 2H), 6.86–6.90 (m, 2H), 5.86 (d,
J = 6.7 Hz, 1H), 5.25 (ddd, J = 10.5, 6.6, 3.8 Hz, 1H), 4.53 (s, 2H), 4.43 (dd, J = 12.2, 5.6 Hz,
H), 3.80 (s, 3H), 3.57 (dd, J = 9.8, 5.3 Hz, 1H), 3.48 (dd, J = 9.8, 5.7 Hz, 1H), 3.08 (dd, J = 11.5,
α]D +8.3 (c 0.44, CHCl ); H-NMR (500 MHz, CDCl ) δ 7.38–7.42
3
3
(
1
7
0
.3 Hz, 1H), 3.04 (dd, J = 13.5, 3.8 Hz, 1H), 2.83 (dd, J = 13.5, 10.7 Hz, 1H), 2.73 (dd, J = 11.5,
.6 Hz, 1H); 13C-NMR (125 MHz, CDCl3)
δ
200.7, 173.6, 159.1, 137.8, 136.4, 131.4, 129.3,
1
28.9, 128.4, 127.78, 127.76, 127.2, 125.5, 113.9, 73.5, 72.5, 71.9, 68.7, 55.2, 51.7, 36.6, 31.7;
+
HRMS (Q–TOF) m/z 506.1458 [(M – H) , C H NO S requires 506.1460].
28
28
4 2
(4R,5R)-5-((benzyloxy)methyl)-4-phenyloxazolidin-2-one (12): A solution of 11 (28.5 mg,
0
.056 mmol, 1.0 equiv.) in THF (1.4 mL, 0.04 M) was treated with Me SiN (22.0 L,
µ
3
3

Molecules 2021, 26, 597
10 of 12
◦
.168 mmol, 3.0 equiv.) and the resulting mixture was heated to reflux at 90 C. After
0
◦
◦
stirring for 5 h at 90 C, the resulting mixture was cooled to 25 C, quenched with the
addition of H O and diluted with CH Cl . The layers were separated, and the aqueous
2
2
2
layer was extracted with CH Cl . The combined organic layers were washed with saturated
2
2
aqueous NaCl, dried over anhydrous Na SO , and concentrated in vacuo. The residue was
2
4
purified by column chromatography (SiO , gradient eluent: 25–50% EtOAc/hexane) to
2
25
1
provide 12 (15.2 mg, 87%) as white oil: [
CDCl3) 7.24–7.32 (m, 4H), 7.16–7.21 (m, 4H), 6.87–6.91 (m, 2H), 5.36 (br s, 1H), 4.98 (dt,
J = 8.1, 5.8 Hz, 1H), 4.94 (d, J = 8.2 Hz, 1H), 4.25 (ABX, 2H, J = 11.7 Hz, ∆ν = 60.0 Hz), 3.83
s, 3H), 3.37 (dd, J = 10.3, 6.1 Hz, 1H), 3.13 (dd, J = 10.3, 5.6 Hz, 1H); 13C-NMR (125 MHz,
α
]D
−
13.3 (c 0.15, MeOH); H-NMR (500 MHz,
δ
(
CDCl3)
δ
160.0, 158.8, 137.4, 128.4, 128.3, 127.9, 127.8, 127.6, 114.1, 78.9, 73.4, 68.6, 57.8, 55.3;
+
HRMS (Q–TOF) m/z 312.1225 [(M − H) , C H NO requires 312.1236].
18
18
4
( )-Cytoxazone (1): A solution of 12 (13 mg, 0.041 mmol, 1 equiv.) in EtOH (1.0 mL,
−
0
1
.04 M) was treated with Pd/C (10%, 65 mg) and hydrogenated at 1 atm. After stirring for
◦
h at 25 C, the resulting mixture was filtered through a pad of Celite and concentrated in
vacuo. The residue was purified by column chromatography (SiO , 75% EtOAc/hexane) to
2
provide (
those of the known synthetic
MeOH) [40] and [
−
)-cytoxazone (1, 8.7 mg, 95%) as a white oil whose spectral data were identical to
25
25
1
[
40
,
41]: [
α
]D
−
72.6 (c 0.11, MeOH) vs [
α
]D
−
70.5 (c 0.8,
8.07 (br
25
1
α
]D
−
70.9 (c 0.4, MeOH) [41]; H-NMR (500 MHz, DMSO-d );
δ
6
s, 1H), 7.14–7.16 (m, 2H), 6.92–6.94 (m, 2H), 5.90 (d, J = 8.3 Hz, 1H), 4.85 (t, J = 5.2 Hz, 1H),
4
.70 (td, J = 8.0, 4.1 Hz, 1H), 3.74 (s, 3H), 2.91–3.00 (m, 2H); 13C-NMR (125 MHz, DMSO-d6)
δ
159.1, 158.9, 129.3, 128.1, 113.7, 80.1, 61.1, 56.2, 55.2; HRMS (Q–TOF) m/z 246.0740 [(M +
+
Na) , C H NNaO requires 246.0742].
11
13
4
4
. Conclusions
In conclusion, we investigated the scope and utility of a combination of the asymmetric
aldol/Curtius protocol in the context of the synthesis of oxazolidin-2-one scaffolds bearing
,5-two vicinal functionalities and their necessary stereogenic centers, due to its interesting
4
structural motifs in natural products and diversity of pharmacological properties. The
developed strategy also allows for a straightforward and concise asymmetric total synthesis
of ( )-cytoxazone in only three steps, making it one of the shortest syntheses reported to
−
date. Continued examination of the synthetic applications of the developed strategy in
the synthesis of bioactive natural products and pharmaceuticals is in progress and will be
disclosed in due course.
Supplementary Materials: The following are available online. Copies of H and 13C-NMR spectra
1
of 1,4,8a–8l,11,12.
Author Contributions: Conceptualization, K.L.; methodology, H.C., H.J., and J.C.; formal analysis,
H.C., H.J., and J.C.; investigation, H.C., H.J., and J.C.; resources, K.L.; data curation, K.L. and H.C.;
writing—original draft preparation, K.L.; writing—review and editing, K.L.; visualization, H.C.;
supervision, K.L.; project administration, K.L.; funding acquisition, K.L. All authors have read and
agreed to the published version of the manuscript.
Funding: This research was supported by National Research Foundation of Korea (NRF) grants
funded by the Korea government (MSIT; No.2020R1A2C1014355) and the 2018 Research Fund of the
Catholic University of Korea.
Data Availability Statement: The data presented in this study are available in Supplementary Material.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds 4,8a–8l are available from the authors.
References
1
.
Slee, A.M.; Wuonola, M.A.; McRipley, R.J.; Zajac, L.; Zawada, M.J.; Bartholomew, P.T.; Gregory, W.A.; Forbes, M. Oxazolidinones,
a New Class of Synthetic Antibacterial Agents: In Vitro and In Vivo Activities of DuP 105 and 721. Antimicrob. Agents Chemother.
1
987, 31, 1791–1797. [CrossRef] [PubMed]

Molecules 2021, 26, 597
11 of 12
2
3
.
.
Muller, M.; Schimz, K.L. Oxazolidinones: A novel class of antibiotics. Cell. Mol. Life Sci. 1999, 56, 280–285. [CrossRef] [PubMed]
Marchese, A.; Schito, G.C. The oxazolidinones as a new family of antimicrobial agent. Clin. Microbiol. Infect. 2001, 7, 66–74.
[CrossRef] [PubMed]
4
5
6
.
.
.
Neu, H.C.; Novelli, A.; Saha, G.; Chin, N.X. In Vitro Acticities of Two Oxazolidinone Antimicrobial Agent, DuP 721 and DuP 105.
Antimicrobal Agents Chemother. 1988, 32, 580–583. [CrossRef]
Bozdogan, B.; Appelbaum, P.C. Oxazolidinones: Activity, mode of action, and mechanism of resistance. Int. J. Antimicrob. Agents
2
004, 23, 113–119. [CrossRef]
Naresh, A.; Rao, M.V.; Kotapalli, S.S.; Ummanni, R.; Rao, B.V. Oxazolidinone derivatives: Cytoxazone-linezolid hybrids induces
apoptosis and senescence in DU145 prostate cells. Eur. J. Med. Chem. 2014, 80, 295–307. [CrossRef]
Clemett, D.; Markham, A. Linezolid. Drugs 2000, 59, 815–827. [CrossRef]
Ford, C.W.; Zurenko, G.E.; Barbachyn, M.R. The Discovery of Linezolid, the First Oxazolidinone Antibacterial Agent. Curr. Drug.
Targets Infect. Disord. 2001, 1, 181–199. [CrossRef]
7
8
.
.
9
.
Noskin, G.A.; Siddiqui, F.; Stosor, V.; Hacek, D.; Peterson, L.R. In Vitro Activities of Linezolid against Important Gram-positive
Bacterial Pathogens Including Vancomycin-Resistant Enterococci. Antimicrob. Agents Chemother. 1999, 43, 2059–2062. [CrossRef]
1
1
0. Burdette, S.D.; Trotman, R. Tedizolid: The first once-daily oxazolidinone class antibiotic. Clin. Infect. Dis. 2015, 61, 1315–1321.
1. Evans, D.A.; Bartroli, J.; Shih, T.L. Enantioselective Aldol Condensations. 2. Erythro-Selective Chiral Aldol Condensations via
Boron Enolates. J. Am. Chem. Soc. 1981, 103, 2127–2129. [CrossRef]
1
1
2. Ager, D.J.; Prakash, I.; Schaad, D.R. 1,2-Amino alcohols and Their Heterocyclic Derivatives as Chiral Auxiliaries in Asymmetric
synthesis. Chem. Rev. 1996, 96, 835–875. [CrossRef] [PubMed]
3. Evans, D.A.; Wu, L.D.; Wiener, J.J.M.; Johnson, J.S.; Ripin, D.H.B.; Tedrow, J.S. A General Method for the Synthesis of Enantiomer-
ically Pure
CrossRef]
β-Substituted, β-Amino Acids through α-Substituted Succinic Acid Derivatives. J. Org. Chem. 1999, 64, 6411–6417.
[
1
1
4. Dinsmore, C.J.; Mercer, S.P. Carboxylation and Mitsunobu Reaction of Amines to Give Carbamates: Retention vs Inversion of
Configuration Is Substituent-Dependent. Org. Lett. 2004, 6, 2885–2888. [CrossRef]
5. Yadav, G.D.; Pawar, S.V. Novelty of immobilized enzymatic synthesis of 3-ethyl-1,3-oxazolidin-2-one using 2-aminoalcohol
and dimethyl carbonate: Mechanism and kinetic modeling of consecutive reactions. J. Mol. Catal. B Enzym. 2014, 109, 62–69.
[CrossRef]
1
1
1
6. Beattie, C.; North, M. Mechanistic Investigation of the Reaction of Epoxides with Heterocumulenes Catalysed by a Bimetallic
Aluminium Salen Complex. Chem. Eur. J. 2014, 20, 8182–8188. [CrossRef]
7. Castro-Osma, J.A.; Earlam, A.; Lara-Sánchez, A.; Otero, A.; North, M. Synthesis of Oxazolidinones from Epoxides and Isocyanates
Catalysed by Aluminium Heteroscorpionate Complexes. Chem. Cat. Chem. 2016, 8, 2100–2108. [CrossRef]
8. Fontana, F.; Chen, C.C.; Aggarwal, V.K. Palladium-Catalyzed Insertion of CO into Vinylaziridines: New Route to 5-
2
Vinyloxazolidinones. Org. Lett. 2011, 13, 3454–3457. [CrossRef]
1
2
2
2
9. Curtius, T. Ueber Stickstoffwasserstoffsäure (Azoimid) N H. Ber. Dtsch. Chem. Ges. 1890, 23, 3023–3033. [CrossRef]
3
0. Curtius, T. Hydrazide und Azide organischer Säuren. J. Prakt. Chem. 1894, 50, 275–294. [CrossRef]
1. Scriven, E.F.V.; Turnbull, K. Azides: Their preparation and synthetic uses. Chem. Rev. 1988, 88, 297–368. [CrossRef]
2. Shioiri, T.; Ninomiya, K.; Yamada, S. Diphenylphosphoryl Azide. A New Convenient Reagent for a Modified Curtius Reaction
and for the Peptide Synthesis. J. Am. Chem. Soc. 1972, 94, 6203–6205. [CrossRef] [PubMed]
2
3. Wolff, O.; Waldvogel, S.R. Reliable Protocol for the Large Scale Synthesis of Diphenylphosphoryl Azide (DPPA). Synthesis 2004
303–1305.
,
1
2
2
4. Cowden, C.J.; Paterson, I. Asymmetric Aldol Reactions Using Boron Enolates. Org. React. 1997, 51, 1–200.
5. Nagao, Y.; Kumagai, T.; Yamada, S.; Fujita, E.; Inoue, Y.; Nagase, Y.; Aoyagi, S.; Abe, T. Investigation of New Chiral 1,3-
Oxazolidine-2-thiones: Analytical Separation and Optical Resolution of Racemic Carboxylic Acids and Amino Acids. J. Chem.
Soc. Perkin Trans. 1 1985, 2361–2367. [CrossRef]
2
6. Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.; Fujita, E. Use of Chiral 1,3-Oxazolidine-2-thiones in the Diastereoselective
Synthesis of Aldols. J. Chem. Soc. Chem. Commun. 1985, 1418–1419. [CrossRef]
2
7. Crimmins, M.T.; King, B.W.; Tabet, E.A.; Chaudhary, K. Asymmetric Aldol Additions: Use of Titanium Tetrachloride and
(
2
−
)-Sparteine for the Soft Enolization of N-Acyl Oxazolidinones, Oxazolidinethiones, and Thiazolidinethiones. J. Org. Chem.
001, 66, 894–902. [CrossRef]
2
2
3
8. Crimmins, M.T.; She, J. An Improved Procedure for Asymmetric Aldol Additions with N-Acyl Oxazolidinones, Oxazo-
lidinethiones and Thiazolidinethiones. Synlett 2004, 1371–1374. [CrossRef]
9. Crimmins, M.T.; Chaudhary, K. Titanium Enolates of Thiazolidinethione Chiral Auxiliaries: Versatile Tools for Asymmetric Aldol
Additions. Org. Lett. 2000, 2, 775–777. [CrossRef]
0. Choi, H.; Jang, H.; Kim, H.; Lee, K. Synthesis of γ-Lactones via the Kowalski Homologation Reaction: Protecting-Group-Free
Divergent Total Syntheses of Eupomatilones-2,5,6, and 3-epi-Eupomatilone-6. Org. Lett. 2019, 21, 7857–7862. [CrossRef]
1. Birkofer, L.; Wegner, P. Trimethylsilyl Azide. Org. Synth. 1970, 50, 107.
2. Kakeya, H.; Morishita, M.; Kobinata, K.; Osono, M.; Ishizuka, M.; Osada, H. Isolation and biological activityof a novel cytokine
modulator, cytoxazone. J. Antibiot. 1998, 51, 1126–1128. [CrossRef] [PubMed]
3
3

Molecules 2021, 26, 597
12 of 12
3
3
3
3
3
3
3
4
3. Sakamoto, Y.; Shiraishi, A.; Seonhee, J.; Nakata, T. Stereoselective syntheses of cytoxazone, a novel cytokine modulator, and its
stereoisomers. Tetrahedron Lett. 1999, 40, 4203–4206. [CrossRef]
4. Kakeya, H.; Morishita, H.; Koshino, T.; Morita, K.; Kobayashi, K.; Osada, H. Cytoxazone: A Novel Cytokine Modulator Containing
a 2-Oxazolidinone Ring Produced by Streptomyces sp. J. Org. Chem. 1999, 64, 1052–1053. [CrossRef] [PubMed]
5. Carda, M.; González, F.; Sánchez, R.; Marco, J.A. Stereoselective synthesis of (
005–1010. [CrossRef]
−
)-Cytoxazone. Tetrahedron Asymmetry 2002, 13,
1
6. Carter, P.H.; LaPorte, J.R.; Scherle, P.A.; Decicco, C.P. A New Synthesis of Cytoxazone and Its Diastereomers Provides Key Initial
SAR Information. Bioorg. Med. Chem. Lett. 2003, 13, 1237–1239. [CrossRef]
7. Boruwa, J.; Borah, J.C.; Kalita, B.; Barua, N.C. Highly regioselective ring opening of epoxides using NaN : A short and efficient
3
synthesis of (–)-Cytoxazone. Tetrahedron Lett. 2004, 45, 7355–7358. [CrossRef]
8. Davies, S.G.; Hughes, D.G.; Nicholson, R.L.; Smith, A.D.; Wright, A.J. Asymmetric synthesis of (4R,5R)-cytoxazone and (4R,5S)-
epi-cytoxazone. Org. Biomol. Chem. 2004, 2, 1549–1553. [CrossRef]
9. Venkataramasubramanian, V.; Kiran, I.N.C.; Sudalai, A. Proline-Catalyzed
Enantiomerically Pure syn- and anti-3-Amino-3-aryl-1,2-alkanediols. Synlett 2015, 26, 355–358.
0. Lingamurthy, M.; Nalliboina, G.R.; Rao, M.V.; Rao, B.V.; Reddy, B.S.; Kumar, H.M.S. DDQ mediated stereoselective intermolecular
benzylic CeN bond formation: Synthesis of ( )-cytoxazone, ( )-4-epi-cytoxazone and their analogues and immunological
α-Aminooxylation of β-Amino Aldehydes: Access to
−
−
evaluation of their cytokine modulating activity. Tetrahedron 2017, 73, 1473–1481. [CrossRef]
4
1. Hidasová, D.; Janák, M.; Jahn, E.; Císa rˇ ová, I.; Jones, P.G.; Jahn, U. Diastereoselective Radical Couplings Enable the Asymmetric
Synthesis of anti-β-Amino-α-hydroxy Carboxylic Acid Derivatives. Eur. J. Org. Chem. 2018, 5222–5230. [CrossRef]