Stereoselective Oxidation of Titanium(IV) Enolates with Oxygen

Article abstract of DOI:10.1055/s-0037-1609966

A novel approach to synthesize enantiomerically pure α-hydroxy carboxylic derivatives is reported. A highly stereoselective oxidation of titanium(IV) enolates from chiral N -acyloxazolidinones is performed with oxygen under simple experimental conditions

Full text of DOI:10.1055/s-0037-1609966

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–F
paper
A
en
A. Gómez-Palomino et al.
Paper
Synthesis
Stereoselective Oxidation of Titanium(IV) Enolates with Oxygen
Alejandro Gómez-Palomino
O
O
O
O
1) TiCl4, i-Pr2NEt, CH2Cl2, 0 °C
R
R
Pedro Romea*
0
0
0
0
0-
0
0
2
0-
2
5
9
9-
1
5
5
O
N
O
N
2) O2 (1 atm), r.t.
Fèlix Urpí*
0
0
0
0
0-
0
0
3
4-
2
8
9
6-
5
0
6
OH
Bn
Bn
Other reagents not required
Departament de Química Inorgànica i Orgànica, Secció
de Química Orgànica, and Institut de Biomedicina (IBUB),
Universitat de Barcelona, Carrer Martí i Franqués 1–11,
08028 Barcelona, Catalonia, Spain
Single diastereomer
8 examples
28–45% yield
felix.urpi@ub.edu
pedro.romea@ub.edu
Received: 13.03.2018
Accepted after revision: 13.04.2018
Published online: 29.05.2018
sodium enolates from chiral N-acyl trifluoromethylated ox-
azolidines with molecular oxygen produced α-hydroxy ad-
ducts with outstanding diastereoselectivities.7 In turn, Itoh
and Zhao used oxygen for the enantioselective phase trans-
fer catalyzed α-hydroxylation of oxindoles and ketones
leading to tertiary alcohols.8 More recently, Lu has reported
a highly efficient hydroxylation of chiral sulfinyl imidates
and amidines with oxygen.9 All of these reported oxidations
involve a heterolytic mechanism that provides the corre-
sponding hydroperoxide intermediates, which must be sub-
sequently reduced to the desired α-hydroxy derivatives.
In this context and by taking advantage of both the bi-
radical character of the titanium(IV) enolates10,11 and our
experience of oxidizing them with TEMPO,12 we aimed to
determine whether the reaction of chiral titanium(IV) eno-
lates with triplet molecular oxygen would yield enantio-
merically pure α-hydroxylated derivatives through a radical
pathway. Thus, we were pleased to observe in exploratory
experiments that bubbling a stream of oxygen through a
solution of the TiCl4-enolate of (S)-4-benzyl-5,5-dimethyl-
N-propanoyl-1,3-oxazolidin-2-one (1a) triggered the de-
sired oxidation at 0 °C (Scheme 1). To our surprise, instead
of the expected hydroperoxide 2a, the hydroxylated deriva-
tive 3a was directly obtained as a single diastereomer with
a yield of 28% (Scheme 1).
DOI: 10.1055/s-0037-1609966; Art ID: ss-2018-t0177-op
Abstract A novel approach to synthesize enantiomerically pure α-hy-
droxy carboxylic derivatives is reported. A highly stereoselective oxida-
tion of titanium(IV) enolates from chiral N-acyloxazolidinones is per-
formed with oxygen under simple experimental conditions that do not
require any reducing steps. The success of this approach depends on
the biradical character of titanium(IV) enolates.
Key words stereoselective synthesis, hydroxylation, titanium eno-
lates, chiral auxiliaries, oxygen, radicals
The chemo-, site-, and stereoselective oxidation of the
carbon backbone of organic molecules is a formidable chal-
lenge that has attracted increasing interest in recent years.1
It goes without saying that the wide range of functional
groups and positions that can be oxidized makes such a
synthetic approach very complicated. Hence, the oxidation
of metal enolates is an appealing way to tackle such a chal-
lenge and gain access to enantiomerically pure α-hydroxy
carbonyl or carboxylic compounds in a straightforward
manner.2 Indeed, this ensures site-selective oxidation of the
Cα position, both the control of the geometry (Z vs E) and
the π-face differentiation of the enolate enable highly ste-
reocontrolled transformations, and the overall reactivity
can be tuned by the appropriate choice of the metal. Tradi-
tionally, the stereoselective oxidation of enolates has been
carried out with N-sulfonyloxaziridines,2–4 but there is a
need for new methods that use environmentally benign ox-
idants. Molecular oxygen is arguably the most suitable can-
didate for such an oxidant as it is an abundant reagent that
does not produce harmful by-products.5 However, despite
such benefits, it has been scarcely used for the stereoselec-
tive hydroxylation of enolates. In pioneering studies, Córdo-
va described the organocatalytic and photosensitized oxi-
dation of cyclohexanones and aldehydes with molecular ox-
ygen.6 Furthermore, Brigaud established that treating
O
O
1) TiCl4, i-Pr2NEt
O
N
2) O2, 0 °C
O
OH
expected
O
O
Bn
2a
O
N
O
O
1) TiCl4, i-Pr2NEt
Bn
1a
O
N
2) O2, 0 °C
OH
observed
Bn
dr > 97:3 28%
3a
Scheme 1 Oxidation of Ti(IV) enolates with molecular oxygen
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

B
A. Gómez-Palomino et al.
Paper
Synthesis
Titanium(IV) enolates prepared by enolization with
TiCl3(i-PrO)/i-Pr2NEt did not add any benefit and milder
TiCl2(i-PrO)2 or TiCl(i-PrO)3 Lewis acids are known to be un-
able to promote an appropriate enolization of such oxazo-
lidinones.13,14 In turn, the oxidation of the corresponding
sodium or boron enolates using the same conditions was
unsuccessful; whereas the oxidation of zirconium(IV) eno-
lates15 produced the α-hydroxylated adduct 3a in a yield of
18%. Remarkably, careful analysis of the crude reaction
mixtures indicated the generation of low, but significant
amounts of the by-products 4 shown in Figure 1.
The use of molecular sieves or the addition of a second
equivalent of TiCl4 or other reagents, such as (EtO)3P, did
not improve the yield. Instead, temperature turned out to
be crucial, since the reaction did not progress at all at tem-
peratures lower than –20 °C. Finally, we also examined the
influence of the amount of oxygen on the yield of the reac-
tion. Surprisingly, both an excess and 1.3 equivalents of ox-
ygen produced the same yield (Table 1, entries 1 and 2),
whereas a substoichiometric amount of oxygen gave 3a in a
40% yield (entry 3). Such close results hinted that both at-
oms of the oxygen molecule were incorporated into the ox-
idized adduct 3a.
O
O
O
O
O
O
Cl
O
Table 1 Influence of the Amount of Oxygen on the Yield of the Reac-
O
N
O
N
N
O
tion
Bn
Bn
4a
Bn
4b
O
O
O
O
1) TiCl4, i-Pr2NEt
Bn
O
O
N
O
O
N
2) O2 (equiv), r.t.
OH
N
O
O
N
Bn
3a
Bn
1a
O
O
Bn
4c
Entry
O2 (equiv)a
Yield (%)b
Figure 1 By-products formed in the oxidation of Ti(IV) enolates with
oxygen
1
2
3
excess
1.3
45
45
40
0.6
A comprehensive optimization of the reaction condi-
tions indicated that the oxidation was much more reliable
by a simple stirring of the solution containing the titani-
um(IV) enolate in an oxygen atmosphere at room tempera-
ture. Indeed, enolization of 1a with TiCl4/i-Pr2NEt at 0 °C for
40 minutes in a nitrogen atmosphere and further stirring of
the resulting deep red solution under an oxygen atmo-
sphere (1 atm) at room temperature for 3 hours produced
the α-hydroxy adduct 3a in a yield of 45% without consum-
ing all the starting material (see Figure 2). Interestingly, the
color of the reacting mixture changed to orange or dark yel-
low, which facilitated the monitoring of the oxidation.
a Estimated amount of O2 based on the equivalence 1 mmol ≈ 22.4 mL.
b Isolated yields.
Although the underlying mechanism of such α-hydrox-
ylation is still unclear, the abovementioned results suggest
that the oxidation of titanium(IV) enolates might be ratio-
nalized by considering the biradical character of such spe-
cies. Indeed, we hypothesized that a radical-like reaction of
triplet oxygen with the biradical titanium enolate II might
trigger the formation of the peroxide III shown in Scheme
2. The observed high π-face selectivity may be due to the
chelated character of II.16 Taking into account a previous re-
port by Adam,17 the internal autoxidation of the titani-
um(III) center of the resulting species might then generate a
peroxytitanate intermediate like IV, which could be respon-
sible for the further oxidation of a titanium(IV) enolate I
that is not yet oxidized.18–20
Aiming to assess the scope of the reaction, we next ap-
plied the optimized reaction conditions to TiCl4-enolates
from N-acyloxazolidinones 1 containing a wide array of R
groups (Scheme 3).17,18 All these reactions provided in mod-
erate yields a single diastereomer of the corresponding oxy-
genated adducts, which were easily isolated by column
chromatography (Scheme 3). The yields from 1a–d indicat-
ed that the reaction is sensitive to the steric hindrance of
the R groups. Otherwise, the benzylic position in 1e (R: Bn),
Figure 2 Oxidation of titanium(IV) enolate of 1a with oxygen
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

C
A. Gómez-Palomino et al.
Paper
Synthesis
O
O
Cl4
Cl4
TiIV
TiIII
O
N
O
O
O
O
OH
R
R
Bn
O
N
O
N
valence
tautomerism
3e
Bn
Bn
I
II
MeOMgBr
Et2O, 0 °C
NaBH4
THF/H2O, 0 °C
Cl4
TiIII
93%
95%
O
O
O2
R
O
O
O
N
O
MeO
HO
Bn
III
OH
OH
5
6
O
O
O
O
1) I
2) H3O+
R
O
Scheme 4 Removal of the chiral auxiliary
R
O
N
O
N
O
OH
Bn
Bn
TiIV
of the corresponding α-hydroxy adducts, which can then be
easily converted into enantiomerically pure and syntheti-
cally useful intermediates. Importantly, the isolation of the
α-hydroxy adducts does not require any additional reduc-
ing agent, suggesting that the overall reaction involves an
internal redox step that is probably linked to the biradical
character of titanium(IV) enolates.
IV
Cl4
Scheme 2 Mechanistic hypothesis
the double and triple carbon bonds in 1f and 1g, respective-
ly, or the ester group in 1h did not affect the result, which
proves the high site-selectivity and chemoselectivity
achieved in this oxidation of the Cα position.
Finally, the smooth removal of the chiral auxiliary from
model adduct 3e, following reported procedures,21 generat-
ed excellent yields of up to 95% of the α-hydroxy ester 5 and
1,2-diol 6 (Scheme 4). This also enabled the S-configuration
of the α-stereocenter to be established.
In summary, we have reported a novel stereoselective
approach of synthesizing α-hydroxy carboxylic derivatives
based on the oxidation of titanium(IV) enolates from chiral
acyl oxazolidinones with environmentally friendly oxygen
using simple experimental conditions. This transformation
produces moderate yields, but in a highly selective manner,
Unless otherwise stated, reactions were conducted in oven-dried
glassware under an inert atmosphere of N2 with anhydrous solvents.
The solvents and reagents were dried and purified, when necessary,
according to standard procedures. All commercial reagents were used
as received. Column chromatography were carried out under low
pressure (flash) conditions and performed on SDS silica gel 60 (35–70
μm). Analytical TLC were carried out on Merck silica gel 60 F254
plates and analyzed by UV (254 nm) and stained with phosphomolyb-
dic acid or p-anisaldehyde. Rf values are approximate. Melting points
were determined with a Stuart Scientific SMP10 or a Gallenkamp ap-
paratus and are uncorrected. Specific rotations ([α]) were determined
at 589 nm and at 20 °C on a PerkinElmer 241 MC polarimeter. IR spec-
tra (Attenuated Total Reflectance, ATR) were recorded on a Nicolet
O
O
O
O
1) TiCl4, i-Pr2NEt, 0 °C, 40 min
R
R
O
N
O
N
2) O2, r.t., 2–5 h
OH
Bn
Bn
1
3
O
O
O
O
O
O
O
O
O
N
O
N
O
N
O
N
Bn
3d 32%
OH
OH
OH
OH
Bn
3a 45%
Bn
Bn
3b 43%
3c 28%
O
O
O
O
O
O
O
O
O
O
N
O
N
O
N
O
N
OMe
OH
OH
OH
OH
Bn
Bn
Bn
Bn
3f 32%
3g 32%
3h 30%
3e 34%
Scheme 3 Oxidation of N-acylated oxazolidinones 1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

D
A. Gómez-Palomino et al.
Paper
Synthesis
6700 FT-IR Thermo Scientific spectrophotometer and only the more
representative frequencies are reported. 1H NMR (400 MHz) and 13C
NMR (100.6 MHz) spectra were recorded on a Varian Mercury 400
spectrometer. Chemical shifts (δ) are quoted in ppm and referenced
to internal TMS (δ 0.00 for 1H NMR) or CDCl3 (δ 77.0 for 13C NMR);
data are reported as follows: integration, peak multiplicity (standard
abbreviations) with coupling constants measured in Hz; when neces-
sary, 2D techniques (COSY and HSQC) were also used to assist with
structure elucidation. High-resolution mass spectra (HRMS) were ob-
tained with an Agilent 1100 spectrometer by the Unitat d’Espectro-
metria de Masses, Universitat de Barcelona.
HRMS (+ESI): m/z [M + H]+ calcd for C15H20NO4: 278.1387; found:
278.1392.
(S)-4-Benzyl-N-[(S)-2-hydroxybutanoyl]-5,5-dimethyl-1,3-oxazoli-
din-2-one (3b)
Prepared according to the General Procedure from (S)-4-benzyl-N-bu-
tanoyl-5,5-dimethyl-1,3-oxazolidin-2-one (1b; 137 mg, 0.5 mmol).
Purification of the residue by column chromatography (hexanes–EtO-
Ac, 80:20) afforded 63 mg (0.22 mmol, 43%) of 3b as a white solid; mp
20
67–68 °C; [α]D –30.7 (c 1.0, CHCl3); Rf = 0.30 (hexanes–EtOAc,
80:20).
IR (ATR): 3412, 2967, 2927, 2874, 1770, 1672, 1352 cm–1
.
Acylation of the Chiral Auxiliary (S)-4-Benzyl-5,5-dimethyl-1,3-
oxazolidin-2-one; General Procedure
1H NMR (400 MHz, CDCl3): δ = 7.34–7.22 (5 H, m), 4.95 (1 H, td, J = 7.6,
3.8 Hz), 4.47 (1 H, dd, J = 9.6, 3.6 Hz), 3.44 (1 H, d, J = 7.6 Hz), 3.20 (1 H,
dd, J = 14.5, 3.6 Hz), 2.93 (1 H, dd, J = 14.5, 9.6 Hz), 1.91–1.81 (1 H, m),
1.68–1.57 (1 H, m), 1.39 (3 H, s), 1.39 (3 H, s), 1.03 (3 H, t, J = 7.4 Hz).
13C NMR (100.6 MHz, CDCl3): δ = 175.0, 152.4, 136.6, 129.0, 128.7,
126.9, 83.5, 71.8, 64.0, 35.0, 28.5, 27.3, 22.1, 9.4.
A 2.5 M solution of n-BuLi in hexanes (2.2 mL, 5.5 mmol) was added
dropwise to a solution of (S)-4-benzyl-5,5-dimethyl-1,3-oxazolidin-
2-one22 (1.03 g, 5.0 mmol) in THF (25 mL) at –78 °C under N2. The
solution was stirred for 15 min and the corresponding acyl chloride
(6.5 mmol) was added dropwise. The reaction mixture was stirred at
–78 °C for 20 min, allowed to warm to r.t., stirred for 2 h, and
quenched with sat. aq NH4Cl (20 mL). The volatiles were removed and
the resulting mixture was partitioned between H2O and EtOAc (20 mL
each), and the aqueous layer was extracted with EtOAc (2 × 20 mL).
The combined organic extracts were washed with sat. aq NaHCO3 (15
mL) and brine (15 mL), dried (MgSO4), filtered and concentrated. The
residue was purified by column chromatography to give the respec-
tive acylated chiral auxiliary 1a–h23 in yields higher than 90%.
HRMS (+ESI): m/z [M + Na]+ calcd for C16H21NO4Na: 314.1363; found:
314.1373.
(S)-4-Benzyl-N-[(S)-2-hydroxy-3-methylbutanoyl]-5,5-dimethyl-
1,3-oxazolidin-2-one (3c)
Prepared according to the General Procedure from (S)-4-benzyl-5,5-
dimethyl-N-(3-methylbutanoyl)-1,3-oxazolidin-2-one (1c; 145 mg,
0.5 mmol). Purification of the residue by column chromatography
(hexanes–EtOAc, 80:20) afforded 43 mg (0.14 mmol, 28%) of 3c as a
Direct Oxidation of 1; General Procedure
20
white solid; mp 65–66 °C; [α]D –18.0 (c 1.0, CHCl3); Rf = 0.30 (hex-
Neat TiCl4 (61 μL, 0.55 mmol) was added dropwise to a solution of re-
spective 1a–h (0.50 mmol) in CH2Cl2 (2 mL) at 0 °C under N2 and the
resultant yellow suspension was stirred for 5 min. Then, i-Pr2NEt (96
μL, 0.55 mmol) was added dropwise and the ensuing dark solution
was stirred for 40 min at 0 °C. The reaction flask was purged with
H2SO4-dried O2 for 5 min at 0 °C and stirring was continued at r.t. for
2–5 h under an O2 atmosphere. The reaction was quenched by the ad-
dition of a sat. aq NH4Cl (2 mL) at r.t. with vigorous stirring. The mix-
ture was partitioned between CH2Cl2 (10 mL) and H2O (10 mL), and
the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic extracts were dried (MgSO4), filtered, and concentrat-
ed. The residue was analyzed by 1H NMR and purified by column
chromatography to afford a single diastereomer of the corresponding
hydroxylated compound 3a–h.
anes–EtOAc, 80:20).
IR (ATR): 3430, 2972, 2923, 2869, 1766, 1694, 1672, 1347 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.34–7.22 (5 H, m), 4.98 (1 H, dd, J =
8.3, 3.3 Hz), 4.46 (1 H, dd, J = 9.7, 3.5 Hz), 3.21 (1 H, dd, J = 14.5, 3.5
Hz), 3.19 (1 H, d, J = 8.3 Hz), 2.94 (1 H, dd, J = 14.5, 9.7 Hz), 2.12–2.04
(1 H, m), 1.38 (6 H, s), 1.09 (3 H, d, J = 6.8 Hz), 0.84 (3 H, d, J = 6.8 Hz).
13C NMR (100.6 MHz, CDCl3): δ = 175.1, 152.2, 136.6, 129.0, 128.7,
126.9, 83.4, 74.7, 64.2, 35.0, 31.4, 28.4, 22.1, 19.7, 15.1.
HRMS (+ESI): m/z [M + Na]+ calcd for C17H23NO4Na: 328.1519; found:
328.1529.
.
(S)-4-Benzyl-N-[(S)-2-cyclopropyl-2-hydroxyacetyl]-5,5-dimethyl-
1,3-oxazolidin-2-one (3d)
Prepared according to the General Procedure from (S)-4-benzyl-N-(2-
cyclopropylacetyl)-5,5-dimethyl-1,3-oxazolidin-2-one (1d; 99 mg,
0.35 mmol). Purification of the residue by column chromatography
(hexanes–EtOAc, 80:20) afforded 28 mg (0.11 mmol, 32%) of 3d as a
white solid; mp 106–108 °C; [α]D20 –30.9 (c 1.0, CHCl3); Rf = 0.20 (hex-
anes–EtOAc, 80:20).
(S)-4-Benzyl-N-[(S)-2-hydroxypropanoyl]-5,5-dimethyl-1,3-oxazo-
lidin-2-one (3a)
Prepared according to the General Procedure from (S)-4-benzyl-N-
propanoyl-5,5-dimethyl-1,3-oxazolidin-2-one (1a; 131 mg, 0.5
mmol). Purification of the residue by column chromatography (hex-
anes–EtOAc, 80:20) afforded 62 mg (0.22 mmol, 45%) of 3a as a white
IR (ATR): 3404, 2963, 2918, 2851, 1780, 1668, 1352, 1160, 1094 cm–1
.
20
solid; mp 45–47 °C; [α]D –36.5 (c 1.1, CHCl3); Rf = 0.20 (hexanes–
EtOAc, 80:20).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.22 (5 H, m), 4.82 (1 H, dd, J =
8.0, 6.1 Hz), 4.49 (1 H, dd, J = 9.6, 3.6 Hz), 3.39 (1 H, d, J = 8.0 Hz), 3.21
(1 H, dd, J = 14.5, 3.6 Hz), 2.95 (1 H, dd, J = 14.5, 9.6 Hz), 1.41 (3 H, s),
1.40 (3 H, s), 1.29–1.22 (1 H, m), 0.61–0.39 (4 H, m).
13C NMR (100.6 MHz, CDCl3): δ = 174.7, 152.6, 136.6, 129.0, 128.7,
126.9, 83.6, 71.4, 64.2, 35.1, 28.5, 22.1, 13.7, 1.5, 0.9.
IR (ATR): 3451, 2982, 2930, 1771, 1694, 1392, 1354, 1275, 1100 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.22 (5 H, m), 5.04 (1 H, quint, J =
6.9 Hz), 4.49 (1 H, dd, J = 9.5, 3.8 Hz), 3.74 (1 H, d, J = 6.9 Hz), 3.18 (1 H,
dd, J = 14.5, 3.8 Hz), 2.93 (1 H, dd, J = 14.5, 9.5 Hz), 1.42 (3 H, d, J = 6.9
Hz), 1.40 (3 H, s), 1.39 (3 H, s).
13C NMR (100.6 MHz, CDCl3): δ = 175.2, 152.7, 136.5, 129.0, 128.7,
126.9, 83.7, 67.2, 64.0, 35.1, 28.6, 22.2, 19.7.
HRMS (+ESI): m/z [M + Na]+ calcd for C17H21NO4Na: 326.1363; found:
326.1359.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

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A. Gómez-Palomino et al.
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Synthesis
(S)-4-Benzyl-N-[(S)-2-hydroxy-3-phenylpropanoyl]-5,5-dimethyl-
HRMS (+ESI): m/z [M + Na]+ calcd for C18H21NO4Na: 338.1363; found:
1,3-oxazolidin-2-one (3e)
338.1377.
Prepared according to the General Procedure from (S)-4-benzyl-5,5-
dimethyl-N-(3-phenylpropanoyl)-1,3-oxazolidin-2-one (1e; 168 mg,
0.5 mmol). Purification of the residue by column chromatography
(hexanes–EtOAc, 80:20) afforded 60 mg (0.17 mmol, 34%) of 3e as a
white solid; mp 98–99 °C; [α]D –17.3 (c 1.0, CHCl3); Rf = 0.30 (hex-
anes–EtOAc, 80:20).
(S)-4-Benzyl-N-[(S)-2-hydroxy-5-methoxy-5-oxopentanoyl]-5,5-
dimethyl-1,3-oxazolidin-2-one (3h)
Prepared according to the General Procedure from (S)-4-benzyl-N-(5-
methoxy-5-oxopentanoyl)-5,5-dimethyl-1,3-oxazolidin-2-one (1h;
166 mg, 0.5 mmol). Purification of the residue by column chromatog-
raphy (hexanes–EtOAc, 80:20) afforded 53 mg (0.15 mmol, 30%) of 3h
20
IR (ATR): 3425, 3056, 3025, 2994, 2972, 2914, 1792, 1677, 1352, 1330,
20
1094 cm–1
.
as a white solid; mp 91–93 °C; [α]D –21.0 (c 1.0, CHCl3); Rf = 0.20
(hexanes–EtOAc, 80:20).
IR (ATR): 3466, 2972, 2918, 2851, 1757, 1703, 1352, 1245 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.34–7.22 (5 H, m), 4.97 (1 H, td, J = 7.8,
3.9 Hz), 4.48 (1 H, dd, J = 9.5, 3.8 Hz), 3.68 (3 H, s), 3.68 (1 H, d, J = 7.8
Hz), 3.18 (1 H, dd, J = 14.5, 3.8 Hz), 2.92 (1 H, dd, J = 14.5, 9.5 Hz),
2.61–2.47 (2 H, m), 2.18–2.10 (1 H, m), 2.00–1.91 (1 H, m), 1.42 (3 H,
s), 1.40 (3 H, s).
1H NMR (400 MHz, CDCl3): δ = 7.34–7.23 (10 H, m), 5.28 (1 H, td, J =
7.9, 4.0 Hz), 4.46 (1 H, dd, J = 9.7, 3.7 Hz), 3.46 (1 H, d, J = 7.9 Hz), 3.20
(1 H, dd, J = 14.2, 3.7 Hz), 3.16 (1 H, dd, J = 13.8, 4.0 Hz), 2.92 (1 H, dd,
J = 14.2, 9.7 Hz), 2.88 (1 H, dd, J = 13.8, 7.9 Hz), 1.40 (3 H, s), 1.37 (3 H,
s).
13C NMR (100.6 MHz, CDCl3): δ = 174.2, 152.4, 136.7, 136.5, 129.5,
129.0, 128.7, 128.3, 126.9, 126.7, 83.5, 71.7, 64.0, 40.2, 35.0, 28.5,
22.2.
.
13C NMR (100.6 MHz, CDCl3): δ = 174.1, 173.6, 152.6, 136.5, 128.9,
128.7, 126.9, 83.7, 69.6, 63.9, 51.6, 35.0, 29.4, 28.5 (2 ×), 22.2.
HRMS (+ESI): m/z [M + H]+ calcd for C21H24NO4: 354.1700; found:
HRMS (+ESI): m/z [M + Na]+ calcd for C18H23NO6Na: 372.1418; found:
354.1705.
372.1430.
(S)-4-Benzyl-N-[(S)-2-hydroxy-5-hexenoyl]-5,5-dimethyl-1,3-ox-
azolidin-2-one (3f)
Methyl (S)-2-Hydroxy-3-phenylpropanoate (5)
Prepared according to the General Procedure from (S)-4-benzyl-N-(5-
hexenoyl)-5,5-dimethyl-1,3-oxazolidin-2-one (1f; 150 mg, 0.5
mmol). Purification of the residue by column chromatography (hex-
anes–EtOAc, 80:20) afforded 51 mg (0.16 mmol, 32%) of 3f as a white
solid; mp 90–92 °C; [α]D –15.1 (c 1.0, CHCl3); Rf = 0.30 (hexanes–
EtOAc, 80:20).
A 3.0 M solution of MeMgBr in Et2O (103 μL, 0.31 mmol) was added to
MeOH (1.0 mL) and stirred at 0 °C for 10 min. Then, a solution of 3e
(0.53 g, 0.15 mmol) in 3:1 CH2Cl2–MeOH (1.5 mL) was added to the
former suspension at 0 °C under N2 and the resultant mixture was
stirred for 5 min. The reaction was quenched with 10% w/w aq
NaHSO3 (1 mL) and concentrated in vacuo. The residue was parti-
tioned between 10% w/w aq NaHSO3 (10 mL) and CH2Cl2 (20 mL). The
organic layer was separated and the aqueous layer extracted with
CH2Cl2 (3 × 20 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated. Purification by column chroma-
tography (hexanes–EtOAc, 85:15) afforded 31 mg (0.15 mmol, 99% re-
covery) of (S)-benzyl-5,5-dimethyl-1,3-oxazolidin-2-one and 25 mg
20
IR (ATR): 3448, 2994, 2972, 2940, 2990, 2851, 1766, 1703, 1361, 1281
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.22 (5 H, m), 5.84–5.75 (1 H, m),
5.07 (1 H, dq, J = 17.1, 1.6 Hz), 5.01–4.95 (2 H, m), 4.47 (1 H, dd, J = 9.6,
3.7 Hz), 3.52 (1 H, d, J = 7.6 Hz), 3.19 (1 H, dd, J = 14.5, 3.7 Hz), 2.93 (1
H, dd, J = 14.5, 9.6 Hz), 2.29–2.24 (2 H, m), 1.94–1.85 (1 H, m), 1.71–
1.62 (1 H, m), 1.40 (3 H, s), 1.39 (3 H, s).
13C NMR (100.6 MHz, CDCl3): δ = 174.9, 152.4, 137.5, 136.6, 129.0,
128.7, 126.9, 115.3, 83.5, 70.2, 64.0, 35.0, 33.1, 29.4, 28.5, 22.1.
20
(0.14 mmol, 93%) of 5 as a white solid; mp 47–48 °C; [α]D –13.1 (c
1.1, CH2Cl2) {Lit.4a [α]D20 –13.7 (c 1.1, CH2Cl2)}.
IR (ATR): 3271, 3018, 2945, 2838, 1748, 1726, 1425, 1273, 1251, 1087
cm–1
.
HRMS (+ESI): m/z [M + Na]+ calcd for C18H23NO4Na: 340.1519; found:
340.1532.
1H NMR (400 MHz, CDCl3): δ = 7.32–7.20 (5 H, m), 4.45 (1 H, ddd, J =
6.8, 6.1, 4.4 Hz), 3.77 (3 H, s), 3.12 (1 H, dd, J = 13.9, 4.4 Hz), 2.96 (1 H,
dd, J = 13.9, 6.8 Hz), 2.74 (1 H, d, J = 6.1 Hz).
13C NMR (100.6 MHz, CDCl3): δ = 174.5, 136.3, 129.4 (2 ×), 128.4 (2 ×),
126.9, 71.2, 52.4, 40.5.
(S)-4-Benzyl-N-[(S)-2-hydroxy-5-hexynoyl]-5,5-dimethyl-1,3-ox-
azolidin-2-one (3g)
Prepared according to the General Procedure from (S)-4-benzyl-N-(5-
hexynoyl)-5,5-dimethyl-1,3-oxazolidin-2-one (1g; 149 mg, 0.5
mmol). Purification of the residue by column chromatography (hex-
anes–EtOAc, 80:20) afforded 51 mg (0.16 mmol, 32%) of 3g as a white
solid; mp 106–108 °C; [α]D20 –16.4 (c 1.0, CHCl3); Rf = 0.30 (hexanes–
EtOAc, 80:20).
HRMS (+ESI): m/z [M + H]+ calcd for C10H16NO3: 198.1125; found:
198.1116.
(S)-3-Phenyl-1,2-propanediol (6)
A solution of 3e (53 mg, 0.15 mmol) in THF (1 mL) was added to a
solution of NaBH4 (34 mg, 0.9 mmol) in THF–H2O (3:1, 2.2 mL) at 0 °C
under N2 and the resultant mixture was stirred at 0 °C for 50 min. The
reaction was quenched by dropwise addition of aq 2 M HCl/brine
solution until bubbling ceased. The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The com-
bined organic layers were washed with brine (10 mL) and the brine
layer was extracted with CH2Cl2 (2 × 10 mL). The combined organic
extracts were dried (MgSO4), filtered, and concentrated. The residue
was purified by column chromatography (hexanes–EtOAc, from 40:60
to 20:80) afforded 30 mg (0.15 mmol, 97% recovery) of (S)-benzyl-
IR (ATR): 3466, 3292, 2949, 2918, 1761, 1699, 1352, 1107 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.22 (5 H, m), 4.99 (1 H, ddd, J =
8.6, 7.1, 3.6 Hz), 4.49 (1 H, dd, J = 9.4, 3.9 Hz), 3.77 (1 H, d, J = 7.1 Hz),
3.18 (1 H, dd, J = 14.5, 3.9 Hz), 2.93 (1 H, dd, J = 14.5, 9.4 Hz), 2.42 (2 H,
td, J = 7.3, 2.6 Hz), 2.10–2.01 (1 H, m), 1.97 (1 H, t, J = 2.6 Hz), 1.87–
1.78 (1 H, m), 1.41 (3 H, s), 1.40 (3 H, s).
13C NMR (100.6 MHz, CDCl3): δ = 173.9, 152.6, 136.4, 129.0, 128.7,
126.9, 83.7, 83.3, 69.5, 68.9, 64.0, 35.0, 32.1, 28.6, 22.2, 14.4.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

F
A. Gómez-Palomino et al.
Paper
Synthesis
5,5-dimethyl-1,3-oxazolidin-2-one and 21 mg (0.14 mmol, 95%) of
(10) (a) Moreira, I. de. P. R.; Bofill, J. M.; Anglada, J. M.; Solsona, J. G.;
Nebot, J.; Romea, P.; Urpí, F. J. Am. Chem. Soc. 2008, 130, 3242.
(b) Heras, C.; Gómez-Palomino, A.; Romea, P.; Urpí, F.; Bofill, J.
M.; Moreira, I. de. P. R. J. Org. Chem. 2017, 82, 8909.
20
(S)-3-phenyl-1,2-propanediol (6) as a clear colorless oil; [α]D –18.3
20
(c 1.3, CHCl3) {Lit.6a [α]D –18.6 (c 1.3, CHCl3)}; Rf = 0.20 (hexanes–
EtOAc, 85:15).
(11) Zakarian has convincingly demonstrated the biradical character
of titanium(IV) and zirconium(IV) enolates in highly stereose-
lective reactions: (a) Beaumont, S.; Ilardi, E. A.; Monroe, L. R.;
Zakarian, A. J. Am. Chem. Soc. 2010, 132, 1482. (b) Gu, Z.;
Herrmann, A. T.; Zakarian, A. Angew. Chem. Int. Ed. 2011, 50,
7136. (c) Herrmann, A. T.; Smith, L. L.; Zakarian, A. J. Am. Chem.
Soc. 2012, 134, 6976. (d) Ilardi, E. A.; Zakarian, A. Chem. Asian J.
2011, 6, 2260.
IR (ATR): 3221, 3024, 2917, 2850, 1495, 1451, 1070, 1036 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.20 (5 H, m), 3.95–3.89 (1 H, m),
3.66 (1 H, dd, J = 11.2, 2.7 Hz), 3.49 (1 H, dd, J = 11.2, 7.0 Hz), 2.80–
2.70 (2 H, m), 2.39 (2 H, br s).
13C NMR (100.6 MHz, CDCl3): δ = 137.7, 129.3 (2 ×), 128.6 (2 ×), 126.6,
73.0, 66.0, 39.8.
HRMS (+ESI): m/z [M + NH4]+ calcd for C9H16NO2: 170.1176; found:
(12) (a) Gómez-Palomino, A.; Pellicena, M.; Romo, J. M.; Solà, R.;
Romea, P.; Urpí, F.; Font-Bardia, M. Chem. Eur. J. 2014, 20, 10153.
(b) Mabe, P. J.; Zakarian, A. Org. Lett. 2014, 16, 516.
170.1176.
(13) Evans, D. A.; Urpí, F.; Somers, T. C.; Clark, J. S.; Bilodeau, M. T.
J. Am. Chem. Soc. 1990, 112, 8215.
Funding Information
(14) Enolization with mild titanium(IV) Lewis acids is only possible
in more acidic α-halo or α-aryl substrates. See, for instance:
(a) Nebot, J.; Romea, P.; Urpí, F. J. Org. Chem. 2009, 74, 7518.
(b) Alvarado, J.; Herrmann, A. T.; Zakarian, A. J. Org. Chem. 2014,
79, 6206.
Financial support from the Spanish Ministerio de Economía y Com-
petitividad (Grant No. CTQ2015-65759-P) and the Generalitat de
Catalunya (2014 SGR586 and 2017SGR 271) as well as a doctorate stu-
dentship to A.G.-P. (APIF, Universitat de Barcelona) are acknowledged.
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(15) Zirconium(IV) enolates from 1a were prepared according the
experimental procedure reported in reference 11b.
(16) Radical α-hydroxylations of non-chelated chiral N-acyloxazolid-
inones with oxygen yield the corresponding adducts with low
diastereoselectivities, see: Kihara, N.; Ollivier, C.; Renaud, P.
Org. Lett. 1999, 1, 1419.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609966.
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(17) Adam, W.; Metz, M.; Prechtl, F.; Renz, M. Synthesis 1994, 563.
(18) Stereoselective oxidation of enolates by peroxide intermediates
has been occasionally proposed in α-hydroxylation reactions
with molecular oxygen. See, for instance: (a) Yang, Y.;
Moinodeen, F.; Chin, W.; Ma, T.; Jiang, Z.; Tan, C.-H. Org. Lett.
2012, 14, 4762. (b) Wang, Y.; Yin, H.; Tang, X.; Wu, Y.; Meng, Q.;
Gao, Z. J. Org. Chem. 2016, 81, 7042. (c) Wang, Y.; Zheng, Z.; Lian,
M.; Yin, H.; Zhao, J.; Meng, Q.; Gao, Z. Green Chem. 2016, 18,
5493. (d) Ding, W.; Lu, L.-Q.; Zhou, Q.-Q.; Wei, Y.; Chen, J.-R.;
Xiao, W.-J. J. Am. Chem. Soc. 2017, 139, 63.
(19) For the role of peroxide intermediates in nonstereoselective
hydroxylation of enolates with molecular oxygen, see: (a) Liang,
Y.-F.; Jiao, N. Angew. Chem. Int. Ed. 2014, 53, 548. (b) Chaudhari,
M. B.; Sutar, Y.; Malpathak, S.; Hazra, A.; Gnanaprakasam, B.
Org. Lett. 2017, 19, 3628.
References
(1) (a) Chen, K.; Baran, P. S. Nature 2009, 459, 824. (b) Newhouse,
T.; Baran, P. S. Angew. Chem. Int. Ed. 2011, 50, 3362. (c) Saint-
Denis, T. G.; Zhu, R.-Y.; Chen, G.; Wu, Q.-F.; Yu, J.-Q. Science
2018, 359, 747.
(2) (a) Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. Org. React.
2003, 62, 1. (b) Smith, A. M. R.; Hii, K. K. Chem. Rev. 2011, 111,
1637.
(3) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919.
(4) (a) Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am. Chem. Soc.
1985, 107, 4346. (b) Zhang, L.; Zhu, L.; Yang, J.; Luo, J.; Hong, R.
J. Org. Chem. 2016, 81, 3890.
(5) (a) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. Rev. 2005,
105, 2329. (b) Bryliakov, K. P. Chem. Rev. 2017, 117, 11406.
(6) (a) Córdova, A.; Sundén, H.; Engqvist, M.; Ibrahem, I.; Casas, J.
J. Am. Chem. Soc. 2004, 126, 8914. (b) Sundén, H.; Engqvist, M.;
Casas, J.; Ibrahem, I.; Córdova, A. Angew. Chem. Int. Ed. 2004, 43,
6532. (c) Córdova, A.; Sundén, H.; Bøvegig, A.; Johansson, M.;
Himo, F. Chem. Eur. J. 2004, 10, 3673.
(7) Lubin, H.; Tessier, A.; Chaume, G.; Pytkowicz, J.; Brigaud, T. Org.
Lett. 2010, 12, 1496.
(8) (a) Sano, D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593. (b) Sim,
S.-B. D.; Wang, M.; Zhao, Y. ACS Catal. 2015, 5, 3609.
(9) Ma, P.-J.; Liu, H.; Xu, Y.-J.; Aisa, H. A.; Lu, C.-D. Org. Lett. 2018, 20,
1236.
(20) For a comprehensive analysis of the copper-catalyzed oxidation
of ketones with oxygen, see: Tsang, A. S.-K.; Kapat, A.;
Schoenebeck, F. J. Am. Chem. Soc. 2016, 138, 518.
(21) For the removal of 5,5-disubstituted oxazolidinones, see:
(a) Davies, S. G.; Sanganee, H. J. Tetrahedron: Asymmetry 1995,
6, 671. (b) Hintermann, T.; Seebach, D. Helv. Chim. Acta 1998, 81,
2093.
(22) SuperQuat chiral auxiliary (S)-4-benzyl-5,5-dimethyl-1,3-oxaz-
olidin-2-one was prepared according to a procedure previously
reported, see: Bull, S. D.; Davies, S. G.; Jones, S.; Polywka, M. E.
C.; Shyam Prasad, R.; Sanganee, H. J. Synlett 1998, 519.
(23) Spectroscopical and analytical data of 1a–h are in agreement
with those reported in the literature, see: (a) Ref. 11. (b) Bull, S.
D.; Davies, S. G.; Nicholson, R. L.; Sanganee, H. J.; Smith, A. D.
Org. Biomol. Chem. 2003, 1, 2886.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F