A mild and metal-free synthesis of chiral 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazines

Article abstract of DOI:10.1016/j.tet.2021.132304

Various functionalized enantiomerically pure 3-hydroxymethyl-1,4-benzoxazine derivatives, including four stereoisomers, were synthesized from chiral 2,3-epoxy-4-trityloxybutanol. The synthesis was mild and metal-free. Yields of 52%–94%, and stereoselectiv

Full text of DOI:10.1016/j.tet.2021.132304

Tetrahedron 93 (2021) 132304
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A mild and metal-free synthesis of chiral 2,3-dihydro-3-
hydroxymethyl-1,4-benzoxazines
Hongyi Zhao 1, Shengnan Li 1, Shihao Cheng, Ziyun Lin, Dongfeng Zhang*,
Haihong Huang**
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB
Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street,
Beijing, 100050, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Various functionalized enantiomerically pure 3-hydroxymethyl-1,4-benzoxazine derivatives, including
four stereoisomers, were synthesized from chiral 2,3-epoxy-4-trityloxybutanol. The synthesis was mild
and metal-free. Yields of 52%e94%, and stereoselectivities of 95% to >99% ee, were obtained. The
mechanism was investigated using online Fourier-transform infrared spectroscopy. This revealed a base-
promoted cyclization to form tricycle-fused benzoxazinyl-oxazolidinone intermediates in situ, followed
by a hydrolysis process. The method can be easily scaled and carried out in a one-pot manner. The
usefulness of the obtained chiral 3-hydroxymethyl-1,4-benzoxazine derivatives as building blocks was
showcased by further derivatization to form unique tricycle-fused benzoxazines.
Received 30 April 2021
Received in revised form
10 June 2021
Accepted 15 June 2021
Available online 19 June 2021
Keywords:
3-Hydroxymethyl-1,4-benzoxazine
Chiral b-amino alcohol motif
© 2021 Elsevier Ltd. All rights reserved.
Metal-free
Cyclization
Hydrolysis
1. Introduction
1,4-dihydropyridine (HEH), with Pd/C as a catalyst [10]. However,
only racemic 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazines
2,3-Dihydro-1,4-benzoxazines are key structural scaffolds that
are frequently found in many bioactive molecules and pharma-
ceutical agents [1]. Some of these compounds with the 2,3-
dihydro-3-hydroxymethyl-1,4-benzoxazine motif exhibit biolog-
ical activities such as antiproliferation [2], apoptotic regulation [3],
adrenoceptor antagonism [4], androgen receptor modulation [5]
and antitumor activity [6] (Fig. 1).
A number of methods for the synthesis of 2,3-dihydro-3-
hydroxymethyl-1,4-benzoxazine analogues have been reported
(Scheme 1). Chiral 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazines
can be obtained from 2-aminophenol and epoxides [7,8]. Enantio-
merically pure 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazines
have been prepared from chiral aziridines via Pd-catalyzed intra-
molecular CeN bond formation [9]. Zhou's group reported the
synthesis of 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazines from
1,2-epoxy-3-(2-nitroaryloxy)propanes in the presence of Hantzsch
could be synthesized using this procedure. Although some efforts
have been devoted to the development of methods for the prepa-
ration of 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine, strategies
for enantioselective synthesis are insufficient. Additionally, the
reported methods suffer from limitations such as high tempera-
tures, use of expensive metals, and limited substrate scope.
Therefore, there is a need for the development of mild, efficient,
and enantioselective syntheses for 2,3-dihydro-3-hydroxymethyl-
1,4-benzoxazines.
The chiral b-amino alcohol motif is a useful building block with
many applications, including the production of various natural
products [11], medicinally active compounds [12], and chiral aux-
iliaries in organic synthesis [13]. In this work, we present our
construction of enantiomerically pure multi-functional 2,3-
dihydro-1,4-benzoxazines with the chiral 1,2-amino alcohol motif
under mild conditions, starting from propyl (2-((3-((trityloxy)
methyl)oxiran-2-yl)methoxy)phenyl)carbamates (Scheme 2).
* Corresponding author.
** Corresponding author.
2. Results and discussion
E-mail addresses: zdf@imm.ac.cn (D. Zhang), joyce@imm.ac.cn (H. Huang).
These authors contributed equally to this work.
1
Previously, we developed an efficient and mild one-pot
https://doi.org/10.1016/j.tet.2021.132304
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H. Zhao, S. Li, S. Cheng et al.
Tetrahedron 93 (2021) 132304
obtained a mixture of tricyclic fused benzoxazinyl-oxazolidinone
and 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine. Considering
the functionalized 1,4-benzoxazine skeleton, we wondered if it
would be possible to obtain pure 2,3-dihydro-3-hydroxymethyl-
1,4-benzoxazine from the epoxide substrate by optimizing the re-
action conditions. First, to optimize the starting material, we
explored the reactivity of carbamates 1aec at room temperature in
the presence of KOH (2 equiv.) and in anhydrous THF under the
protection of argon (Table 1, entries 1e3). We found that the
desired product 2a was isolated with a yield of 78% and 98% ee
when n-propyl carbamate 1a was used (entry 1), although 6% of the
tricyclic compound 3 was obtained. However, when i-propyl
carbamate 1b and t-butyl carbamate 1c were used as raw materials,
much more tricyclic product 3 was observed in both reactions, and
the corresponding product 2a was obtained with a yield of about
60% (entries 2e3). These results indicate that steric hindrance has a
large influence on the reactivity, and the carbamate with a small
ester group benefits the desired reaction. We continued our study
by choosing 1a as the model substrate. After briefly screening the
solvent in the presence of KOH (entries 4e6), a slightly improved
yield of 2a was achieved in MeCN (entry 6 vs 3). However, a large
amount of solid precipitate formed in MeCN led to difficult stirring.
This suggests that MeCN is not a good solvent for large-scale re-
action. Next, we investigated the influence of the base on the re-
action (entries 7e9). The results show that potassium alkali results
Fig.
1. Representative
compounds
with
2,3-dihydro-3-hydroxymethyl-1,4-
benzoxazine scaffolds.
convergent synthesis for benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one
derivatives [14]. We achieved the cyclization step by using t-
BuOLi (Scheme 2). When screening bases for cyclization using
benzyl carbamate as the starting material and 1.5 equiv. of KOH, we
Scheme 1. Reported strategies for the construction of 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine scaffolds.
Scheme 2. Synthesis of benzo[b]oxazolo[3,4-d][1,4]oxazin-1-ones and 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazines.
2

H. Zhao, S. Li, S. Cheng et al.
Tetrahedron 93 (2021) 132304
Table 1
Optimization of the reaction conditionsa.
entry
substrate
base
equiv.
solvent
ratio of 1/2a/3b
yieldc(%)
ee%
1
2
3
4
5
6
7
8
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
KOH
KOH
KOH
KOH
KOH
KOH
NaOH
EtOK
EtONa
KOH
KOH
2
2
2
2
2
2
2
2
THF
THF
THF
DMF
Dioxane
MeCN
THF
THF
THF
-/94/6
78
60
66
70
e
98
e
-/75/25
-/80/20
-/84/16
38/43/19
-/91/9
12/51/37
-/79/21
15/58/27
-/100/-
-/42/58
e
e
e
84
e
98
e
60
e
e
9
2
2.5
2.5
e
10
THF
THF
94
e
98
e
11d
a
Reaction conditions: 1 (0.4 mmol), anhydrous solvent (5 mL), Ar, rt, 4 h. Substrates 1aec were prepared from compounds A1e3 and B1 according to the literature [14]
(Supporting Information Scheme S1).
b
Determined by 1H NMR.
Isolated yields.
Analytically pure THF, 11 h.
c
d
in greater conversion of starting material than sodium alkali, with
KOH resulting in the greatest conversion. Upon increasing the
amount of KOH to 2.5 equiv., product 2a was obtained with a yield
of 94% and 98% ee (entry 10). In addition, analytically pure THF
(entry 11) was also investigated. However, it took 9 h to finish the
transformation of the substrate 1a to the intermediate 3, and the
intermediate 3 could not convert to product 2a completely, even
prolonging the reaction time to 11 h. Therefore, anhydrous THF was
crucial for the reaction. On the basis of these studies, the optimal
reaction conditions for the preparation of 2a were established, as
shown in entry 10.
Having optimized the reaction conditions, we next investigated
the reaction scope. There are two chiral centers in the epoxy
structure of the substrate, and we first explored the influence of the
configuration of these on the reactivity (Scheme 3). Substrates 1def
were prepared from compounds A1 and B2e4 according to the
literature [14] (Supporting Information Scheme S2). A longer re-
action time was needed to produce (1R, 3R)-2c or (1S, 3S)-2d
compared with the time needed to produce (1R, 3S)-2a or (1S, 3R)-
2b. The three stereoisomers 2bed were obtained with yields of
67%e85% and enantioselectivities of 96%e97% ee, providing a
general approach for accessing different chiral 1,4-benzoxazine
aromatic ring, a long reaction time up to 44 h was needed to pro-
duce 2i with a yield of 52% and 97% ee. We suggest that the reac-
tivity was mainly affected by the steric hindrance exemplified by 2i
vs 2jel. The tert-butoxycarbonyl group and piperidyl group were
also tolerated by the reaction, giving the corresponding products 2s
and 2t with yields of 75% and 78%, respectively. The absolute
configuration of compound 2j was confirmed by X-ray crystallog-
raphy. Substrates 1gev were prepared from compounds A4e19 and
B1 according to the literature [14] (Supporting Information Scheme
S3).
To demonstrate the usefulness of the obtained chiral function-
alized 1,4-benzoxazine derivatives as building blocks, we used
bromine-containing compound 2k as a substrate to expand new
three series of tricyclic fused derivatives (Scheme 4). First, 2k was
reacted with paraformaldehyde [15] to obtain benzoxazinyl-
oxazolidine 4 with a yield of 52%. Second, 2k was treated with
bromoethylsulfonium salt [16], and benzoxazinyl-morpholine 5
was obtained with a yield of 52%. Compound 2k can also react with
ethyl chloroacetate [17] in the presence of t-BuOK to afford the
desired product benzoxazinyl-morpholinone 6 with a yield of 59%.
The potential of 2k in a diverse range of synthesis applications
shows that the multi-functional chiral 1,4-benzoxazine derivatives
are promising building blocks which will facilitate the establish-
ment of a diverse library of bioactive samples.
Next, the scalability of the method was explored (Scheme 5).
The reaction was extended up to the gram-scale (up to 3.4 g) and
the product 2k was obtained with a yield of 97% and enantiose-
lectivity of 98% ee. To further simplify the reaction, we investigated
the possibility of carrying it out in a one-pot manner by adding KOH
(5 equiv.) directly to the Mitsunobu reaction mixture of propyl (4-
bromo-2-hydroxyphenyl)carbamate (A10) and ((2R,3S)-3-((trity-
loxy)methyl)oxiran-2-yl)methanol (B1). This reaction proceeded
successfully, and 2k was obtained with a yield of 87% without the
loss of any enantiomeric excess (98% ee). This further confirms the
convenience of the protocol in this study.
bearing
b-amino alcohol units. Next, substrates with different
substituents on the phenyl ring were examined (Scheme 3).
Generally, both electron-withdrawing groups and electron-
donating groups on the benzene rings were compatible with the
reaction conditions, delivering the desired products (2eet) with
yields of 52%e92% and 95% to >99% ee. Although a longer reaction
time was required (11e36 h), the expected products were isolated
with yields of 69%e92% (2eeh) in the presence of electron-
donating methoxy and methyl groups on the benzene ring. With
electron-withdrawing substituents on the phenyl ring, the reaction
proceeded smoothly compared to that of the substrates with
electron-donating groups, which the desired benzoxazines (2jer)
were afforded in 3.5e5.5 h. Unexpectedly, for the substrate with
bromine at the ortho-position to the carbamate group on the
In the light of our experimental observations, we propose that
3

H. Zhao, S. Li, S. Cheng et al.
Tetrahedron 93 (2021) 132304
Scheme 3. Synthesis of products 2beta.
Scheme 4. Diverse synthesis applications of building block 2k.
the reaction involves a cyclization followed by a hydrolysis process.
To verify this, online Fourier-transform infrared spectroscopy (FTIR)
was used to monitor the reaction using 1a and KOH in anhydrous
THF. First, we collected FTIR data for the starting material 1a, the
intermediate 3 and the product 2a in THF. ConcIRT and 3D surface
plot analyses were used to track changes in the absorbance profiles
of 1a, 3 and 2a over time. These changes are shown in Figs. 2 and 3.
After adding KOH, the peak height at 1737 cmꢀ1 (C]O bond of 1a,
4

H. Zhao, S. Li, S. Cheng et al.
Tetrahedron 93 (2021) 132304
Scheme 5. Gram-scale and one-pot preparation of 2k.
Fig. 2. ConcIRT component profiles of the reaction.
Fig. 3. In situ IR 3D surface plot of the reaction.
blue line) decreased over 1 h. Meanwhile, the peak height at
1778 cmꢀ1 (C]O bond of 3, red line) increased, reached a peak after
1 h, and then decreased. This demonstrates the formation of the
intermediate 3. The peak heights at 1322 cmꢀ1 and 1493 cmꢀ1
increased over this time because of the formation of product 2a. On
the basis of this experiment, we concluded that the reaction pro-
ceeds via the cyclization of 1a to generate the intermediate 3, and
then 3 undergoes a hydrolysis process to produce the final product
2a.
3. Conclusion
In conclusion, we have developed a simple and metal-free
strategy for the synthesis of a series of chiral multi-functional
2,3-dihydro-1,4-benzoxazines containing the 1,2-amino alcohol
unit. The reaction proceeds smoothly under mild conditions with
yields of 52%e94% and 95% to >99% ee. The reaction has potential
for the preparation of the desired product from phenol derivatives
and ((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)methanol using
a
5

H. Zhao, S. Li, S. Cheng et al.
Tetrahedron 93 (2021) 132304
one-pot convergent cyclization procedure. Furthermore, tricyclic
fused benzoxazinyl-oxazolidine, benzoxazinyl-morpholine and
benzoxazinyl-morpholinone have been prepared conveniently
from 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazine. Mechanistic
investigation reveals a base-promoted cyclization to form the tri-
cyclic fused benzoxazinyl-oxazolidinone intermediates in situ, fol-
lowed by a hydrolysis process. Applications of these functionalized
optically active 2,3-dihydro-3-hydroxymethyl-1,4-benzoxazines
will be the subject of future investigations in our laboratory.
Compound A5 was prepared from 2-amino-5-methylphenol
following the preparation method of A1. Flash column chroma-
tography was performed eluting the column with 25% EtOAc in PE.
White solid (1.58 g, 93%). 1H NMR (400 MHz, DMSO-d6)
d: 9.49 (s,
1 H), 8.10 (s, 1 H), 7.36 (d, J ¼ 8.0 Hz, 1 H), 6.64 (d, J ¼ 1.6 Hz, 1 H),
6.56 (dd, J ¼ 1.6, 8.4 Hz, 1 H), 3.99 (t, J ¼ 6.8 Hz, 2 H), 2.18 (s, 3 H),
1.65e1.56 (m, 2 H), 0.91 (t, J ¼ 7.2 Hz, 3 H). HR-MS (ESI): m/z [M þ
H]þ calcd for C11H16NO3: 210.1125; found: 210.1122.
Propyl (2-hydroxy-5-methoxyphenyl)carbamate (A6). Com-
pound A6 was prepared from 2-amino-4-methoxyphenol following
the preparation method of A1. Flash column chromatography was
performed eluting the column with 15% EtOAc in PE. Pink solid
4. Experimental section
Unless otherwise stated, all the solvents and reagents were
purchased from commercial suppliers and were used without
further purification. All melting points were measured with a micro
melting point apparatus (MP-J3, Yanaco) and were uncorrected. 1H
NMR or 13C NMR spectra were recorded on Varian 400 MHz or
500 MHz spectrometer using CDCl3, DMSO-d6 or acetone-d6 as
solvents. HR-MS spectra were obtained on a Thermo Fisher Exactive
Plus mass spectrometer (ESI, ThermoFisher Scientific, Bremen,
Germany). Optical rotations were measured with a Rudolph
Research Analytical (Autopol IV-T).
(1.45 g, 90%). 1H NMR (400 MHz, DMSO-d6)
d: 9.21 (s, 1 H), 8.12 (s,
1 H), 7.28 (d, J ¼ 2.0 Hz,1 H), 6.74 (d, J ¼ 8.8 Hz,1 H), 6.48 (dd, J ¼ 3.2,
8.8 Hz, 1 H), 4.02 (t, J ¼ 6.8 Hz, 2 H), 3.65 (s, 3 H), 1.66e1.58 (m, 2 H),
0.92 (t, J ¼ 7.6 Hz, 3 H). HR-MS (ESI): m/z [M ꢀ H]- calcd for
C
11H14NO4: 224.0917; found: 224.0915.
Propyl (2-hydroxy-4-methoxyphenyl)carbamate (A7).
A
mixture of 5-methoxy-2-nitrophenol (1 g, 5.9 mmol), Raney nickel
(0.3 g) and THF (10 mL) was hydrogenated at 20e50 psi for 5 h. The
reaction mixture was filtered into a flask containing sodium bi-
carbonate (1 g, 11.8 mmol) and water (15 mL) under ice bath,
protected by argon. Propyl chloroformate (0.69 mL, 6.2 mmol) was
added dropwise, and the mixture was stirred for 2 h. Ethyl acetate
was added, and then the organic phase was washed with water and
brine, dried over anhydrous sodium sulfate, filtered and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy (20% EtOAc in PE) to give A7 (1.03 g, 77%) as an orange solid.
4.1. Preparation of phenol derivatives A1e19
Propyl (2-hydroxyphenyl)carbamate (A1). A mixture of 2-
aminophenol (2.7 g, 25 mmol), sodium bicarbonate (4.2 g,
50 mmol), THF (30 mL) and water (15 mL) was cooled in an ice bath
under the protection of argon. Propyl chloroformate (2.9 mL,
26 mmol) was added in dropwise to the above reaction mixture.
After completion monitored by TLC, ethyl acetate was added, and
the organic phase was washed with water and brine, dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The crude
product was purified by column chromatography (25% EtOAc in PE)
to give A1 (4.5 g, 92%) as a white solid. 1H NMR (400 MHz, DMSO-
1H NMR (400 MHz, DMSO-d6)
d: 9.57 (s, 1 H), 8.11 (brs, 1 H), 7.26 (d,
J ¼ 6.0 Hz, 1 H), 6.41 (d, J ¼ 2.8 Hz,1 H), 6.34 (dd, J ¼ 2.8, 8.4 Hz, 1 H),
3.97 (t, J ¼ 6.8 Hz, 2 H), 3.67 (s, 3 H), 1.64e1.55 (m, 2 H), 0.91 (t,
J ¼ 7.2 Hz, 3 H). HR-MS (ESI): m/z [M ꢀ H]- calcd for C11H14NO4:
224.0917; found: 224.0917.
Propyl (2-bromo-6-hydroxyphenyl)carbamate (A8). To
a
mixture of 2-amino-3-bromophenol (1 g, 5.3 mmol) and calcium
carbonate powder (330 mg, 3.3 mmol) in 1,4-dioxane (6 mL) was
added propyl chloroformate (0.62 mL, 5.6 mmol). The reaction
mixture was heated at 70 ꢁC. After completion monitored by TLC,
water was added. The resulting mixture was extracted with ethyl
acetate, and then the organic phase was washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated in vacuo. The
crude product was purified by column chromatography (10% EtOAc
in PE) to give A8 (1.35 g, 92%) as a white solid. 1H NMR (400 MHz,
d6)
d
: 9.66 (s, 1 H), 8.16 (s, 1 H), 7.55 (d, J ¼ 7.6 Hz, 1 H), 6.92e6.88
(m, 1 H), 6.83 (dd, J ¼ 1.6, 8.0 Hz, 1 H), 6.79e6.73 (m, 1 H), 4.01 (t,
J ¼ 6.8 Hz, 2 H), 1.66e1.57 (m, 2 H), 0.92 (t, J ¼ 7.6 Hz, 3 H). HR-MS
(ESI): m/z [M þ H]þ calcd for C10H14NO3: 196.0968; found:
196.0967.
Isopropyl (2-hydroxyphenyl)carbamate (A2). Compound A2
was prepared from 2-aminophenol and isopropyl chloroformate
following the preparation method of A1. Flash column chroma-
tography was performed eluting the column with 20% EtOAc in PE.
DMSO-d6)
d: 9.82 (s, 1 H), 8.49 (brs, 1 H), 7.04 (dd, J ¼ 1.6, 8.0 Hz,
Yellow solid (3.2 g, 82%). 1H NMR (400 MHz, DMSO-d6)
d: 9.67 (s,
1 H), 7.00 (t, J ¼ 8.0 Hz, 1 H), 6.84 (dd, J ¼ 2.0, 8.0 Hz, 1 H), 3.93 (t,
J ¼ 6.4 Hz, 2 H), 1.57 (brs, 2 H), 0.88 (brs, 3 H). HR-MS (ESI): m/z
[MþH]þ calcd for C10H13BrNO3: 274.0073; found: 274.0064.
Propyl (5-bromo-2-hydroxyphenyl)carbamate (A9). Com-
pound A9 was prepared from 2-amino-4-bromophenol following
the preparation method of A1. Flash column chromatography was
performed eluting the column with 20% EtOAc in PE. Off-white
1 H), 8.03 (s, 1 H), 7.56 (d, J ¼ 7.6 Hz, 1 H), 6.91e6.73 (m, 3 H),
4.89e4.83 (m, 1 H), 1.24 (d, J ¼ 6.4 Hz, 6 H). HR-MS (ESI): m/z [M þ
H]þ calcd for C10H14NO3: 196.0968; found: 196.0970.
tert-Butyl (2-hydroxyphenyl)carbamate (A3). To a suspension
of 2-aminophenol (7.63 g, 70 mmol) in DCM (80 mL) was added a
solution of Boc2O (15.3 g, 70 mmol) in DCM (20 mL). The mixture
was stirred at room temperature overnight. After concentration,
the residue was purified by column chromatography (10e20%
EtOAc in PE) to give A3 (13.8 g, 95%) as an off-white solid. 1H NMR
solid (1.12 g, 77%). 1H NMR (400 MHz, DMSO-d6)
d: 10.08 (s, 1 H),
8.33 (s, 1 H), 7.80 (d, J ¼ 2.0 Hz, 1 H), 7.05 (dd, J ¼ 2.4, 8.8 Hz, 1 H),
6.78 (d, J ¼ 8.4 Hz, 1 H), 4.03 (t, J ¼ 6.8 Hz, 2 H), 1.67e1.58 (m, 2 H),
0.92 (t, J ¼ 7.6 Hz, 3 H). HR-MS (ESI): m/z [M ꢀ H]- calcd for
(400 MHz, CDCl3) d: 8.12 (brs, 1 H), 7.10e7.01 (m, 2 H), 6.97 (dd,
J ¼ 1.2, 8.4 Hz, 1 H), 6.89e6.81 (m, 1 H), 6.63 (brs, 1 H), 1.53 (s, 9 H).
Propyl (2-hydroxy-5-methylphenyl)carbamate (A4). Com-
pound A4 was prepared from 2-amino-4-methylphenol following
the preparation method of A1. Flash column chromatography was
performed eluting the column with 15% EtOAc in PE. Pink solid
C
10H11BrNO3: 271.9917; found: 271.9923.
Propyl (4-bromo-2-hydroxyphenyl)carbamate (A10). Com-
pound A10 was prepared from 2-amino-5-bromophenol following
the preparation method of A1. Flash column chromatography was
performed eluting the column with 15% EtOAc in PE. Off-white solid
(1.55 g, 92%). 1H NMR (400 MHz, DMSO-d6)
d: 9.39 (s, 1 H), 8.10 (s,
(1.17 g, 81%). 1H NMR (400 MHz, DMSO-d6)
d: 10.22 (s, 1 H), 8.29 (s,
1 H), 7.38 (s, 1 H), 6.70 (s, 2 H), 4.00 (t, J ¼ 6.8 Hz, 2 H), 2.18 (s, 3 H),
1.65e1.57 (m, 2 H), 0.92 (t, J ¼ 7.6 Hz, 3 H). HR-MS (ESI): m/z [M þ
H]þ calcd for C11H16NO3: 210.1125; found: 210.1121.
1 H), 7.52 (d, J ¼ 8.4 Hz, 1 H), 6.99e6.91 (m, 2 H), 4.01 (t, J ¼ 6.8 Hz,
2 H), 1.66e1.57 (m, 2 H), 0.92 (t, J ¼ 7.6 Hz, 3 H). HR-MS (ESI): m/z
[M ꢀ H]- calcd for C10H11BrNO3: 271.9917; found: 271.9921.
Propyl
(2-hydroxy-4-methylphenyl)carbamate
(A5).
Propyl
(3-bromo-2-hydroxyphenyl)carbamate
(A11).
6

H. Zhao, S. Li, S. Cheng et al.
Tetrahedron 93 (2021) 132304
Compound A11 was prepared from 2-amino-6-bromophenol
following the preparation method of A1. Flash column chroma-
tography was performed eluting the column with 8e15% EtOAc in
EtOAc in PE. White solid (415 mg, 33%). 1H NMR (400 MHz, DMSO-
d6)
d: 10.21 (s, 1 H), 8.35 (s, 1 H), 7.81 (d, J ¼ 8.4 Hz, 1 H), 7.39 (d,
J ¼ 2.0 Hz, 1 H), 7.35 (dd, J ¼ 2.0, 8.4 Hz, 1 H), 4.04 (t, J ¼ 6.8 Hz, 2 H),
1.68e1.59 (m, 2 H),1.52 (s, 9 H), 0.93 (t, J ¼ 7.6 Hz, 3 H). HR-MS (ESI):
m/z [M ꢀ H]- calcd for C15H20NO5: 294.1336; found: 294.1341.
Propyl (2-hydroxy-4-(piperidin-1-yl)phenyl)carbamate (A19).
Compound A19 was prepared from 2-nitro-5-(piperidin-1-yl)
phenol following the preparation method of A7. Flash column
chromatography was performed eluting the column with 15%
EtOAc in PE. Lilac solid (1.75 g, 80%). 1H NMR (400 MHz, DMSO-d6)
PE. Off-white solid (900 mg, 62%). 1H NMR (400 MHz, DMSO-d6)
d:
9.47 (s, 1 H), 8.72 (brs, 1 H), 7.42 (d, J ¼ 7.6 Hz, 1 H), 7.27 (dd, J ¼ 1.6,
8.0 Hz, 1 H), 6.76 (t, J ¼ 8.0 Hz, 1 H), 4.03 (t, J ¼ 6.8 Hz, 2 H),
1.67e1.58 (m, 2 H), 0.92 (t, J ¼ 7.6 Hz, 3 H). HR-MS (ESI): m/z
[M ꢀ H]- calcd for C10H11BrNO3: 271.9917; found: 271.9923.
Propyl (5-fluoro-2-hydroxyphenyl)carbamate (A12). Com-
pound A12 was prepared from 2-amino-4-fluorophenol following
the preparation method of A1. Flash column chromatography was
performed eluting the column with 10e20% EtOAc in PE. Purple
d
: 9.24 (s, 1 H), 8.05 (brs, 1 H), 7.16 (brs, 1 H), 6.39 (d, J ¼ 2.8 Hz, 1 H),
6.34 (dd, J ¼ 2.4, 8.8 Hz, 1 H), 3.96 (t, J ¼ 6.8 Hz, 2 H), 3.01 (t,
J ¼ 5.6 Hz, 4 H), 1.64e1.47 (m, 8 H), 0.91 (t, J ¼ 7.6 Hz, 3 H). HR-MS
(ESI): m/z [M þ H]þ calcd for C15H23N2O3: 279.1703; found:
279.1700.
solid (1.25 g, 74%). 1H NMR (400 MHz, DMSO-d6)
d: 9.75 (s, 1 H),
8.29 (s, 1 H), 7.51 (dd, J ¼ 2.8, 10.8 Hz, 1 H), 6.80 (dd, J ¼ 5.6, 8.8 Hz,
1 H), 6.74e6.67 (m, 1 H), 4.03 (t, J ¼ 6.8 Hz, 2 H), 1.67e1.58 (m, 2 H),
0.92 (t, J ¼ 7.6 Hz, 3 H). HR-MS (ESI): m/z [M ꢀ H]- calcd for
C
10H11FNO3: 212.0717; found: 212.0714.
4.2. Preparation of alcohol derivatives B1e4
Propyl (4-fluoro-2-hydroxyphenyl)carbamate (A13). Com-
pound A13 was prepared from 2-amino-5-fluorophenol following
the preparation method of A1. Flash column chromatography was
performed eluting the column with 7e15% EtOAc in PE. Pink solid
Compounds B1e4 were prepared in accordance with the pro-
cedures in our previous work [14].
(2R,3S)-(3-((Trityloxy)methyl)oxiran-2-yl)methanol (B1). (Z)-
4-(trityloxy)but-2-en-1-ol and D-(ꢀ)-diethyl tartrate were used to
undergo the Sharpless oxidation reaction. After solution workup,
the title compound B1 was obtained as an off-white solid by trit-
uration with a mixture of hexane and ethyl acetate. The corre-
(1.44 g, 86%). 1H NMR (400 MHz, DMSO-d6)
d: 10.12 (brs, 1 H), 8.25
(brs, 1 H), 7.43 (brs, 1 H), 6.64e6.56 (m, 2 H), 3.99 (t, J ¼ 6.8 Hz, 2 H),
1.65e1.58 (m, 2 H), 0.91 (t, J ¼ 7.6 Hz, 3 H). HR-MS (ESI): m/z
[M ꢀ H]- calcd for C10H11FNO3: 212.0717; found: 212.0716.
Propyl (2-hydroxy-5-nitrophenyl)carbamate (A14). Compound
A14 was prepared from 2-amino-4-nitrophenol following the
preparation method of A8. Flash column chromatography was
performed eluting the column with 35% EtOAc in PE. Pale yellow
sponding alcohol was analyzed by Chiral HPLC (IC, 5 mm,
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 90/10; flow rate:
1 mL/min;
l
¼ 220 nm; T ¼ 17 ꢁC): tR ¼ 12.82 min (97.86%),
14.74 min (2.14%). The enantiomeric purity of B1 was determined to
be 96% ee. [
20
solid (1.15 g, 74%). 1H NMR (400 MHz, DMSO-d6)
d: 11.52 (s, 1 H),
a]
¼ þ32.3 (c 1, CHCl3).
D
8.66 (s, 1 H), 8.63 (d, J ¼ 2.8 Hz, 1 H), 7.88 (dd, J ¼ 2.8, 8.8 Hz, 1 H),
6.99 (d, J ¼ 8.8 Hz, 1 H), 4.07 (t, J ¼ 6.8 Hz, 2 H), 1.69e1.60 (m, 2 H),
0.94 (t, J ¼ 7.6 Hz, 3 H). HR-MS (ESI): m/z [M ꢀ H]- calcd for
(2S,3R)-(3-((Trityloxy)methyl)oxiran-2-yl)methanol
(B2).
Compound B2 was prepared from (Z)-4-(trityloxy)but-2-en-1-ol
and L-(þ)-diethyl tartrate. The enantiomeric purity of B2 was
24
C
10H11N2O5: 239.0662; found: 239.0662.
determined to be 97% ee. [
a
]
¼ ꢀ31.1 (c 1, CHCl3).
D
Propyl (2-hydroxy-4-nitrophenyl)carbamate (A15). Compound
((2S,3S)-3-((Trityloxy)methyl)oxiran-2-yl)methanol
(B3).
A15 was prepared from 2-amino-5-nitrophenol following the
preparation method of A8. Flash column chromatography was
performed eluting the column with 30% EtOAc in PE. Pink solid
Compound B3 was prepared from (E)-4-(trityloxy)but-2-en-1-ol
and L-(þ)-diethyl tartrate. The corresponding alcohol was
analyzed by Chiral HPLC (OZ-H, 5
m
m, 4.6 mm ꢂ 250mm; eluent:
(1.3 g, 83%). 1H NMR (400 MHz, DMSO-d6)
d: 10.96 (s,1 H), 8.70 (brs,
hexane/isopropanol, 97/3; flow rate: 1 mL/min;
l
¼ 220 nm;
1 H), 8.02 (d, J ¼ 9.2 Hz, 1 H), 7.74 (dd, J ¼ 2.8, 9.2 Hz, 1 H), 7.64 (d,
J ¼ 2.8 Hz, 1 H), 4.08 (t, J ¼ 6.8 Hz, 2 H), 1.69e1.60 (m, 2 H), 0.94 (t,
J ¼ 7.6 Hz, 3 H). HR-MS (ESI): m/z [M ꢀ H]- calcd for C10H11N2O5:
239.0662; found: 239.0663.
T ¼ 20 ꢁC): tR ¼ 18.62 min (1.72%), 21.26 min (98.28%).The enan-
25
tiomeric purity of B3 was determined to be 97% ee. [
1, EtOAc).
a
]
¼ ꢀ10.5 (c
D
((2R,3R)-3-((Trityloxy)methyl)oxiran-2-yl)methanol
(B4).
Propyl (3,4-difluoro-2-hydroxyphenyl)carbamate (A16). Com-
pound A16 was prepared from 2,3-difluoro-6-nitrophenol
following the preparation method of A7. Flash column chroma-
tography was performed eluting the column with 10% EtOAc in PE.
Compound B4 was prepared from (E)-4-(trityloxy)but-2-en-1-ol
and D-(ꢀ)-diethyl tartrate. The enantiomeric purity of B4 was
25
determined to be 98% ee. [
a
]
¼ þ9.4 (c 1, EtOAc).
D
Yellow solid (407 mg, 31%). 1H NMR (400 MHz, DMSO-d6)
d: 10.28
4.3. Preparation of ether derivatives 1aev
(s, 1 H), 8.60 (brs, 1 H), 7.23 (t, J ¼ 6.8 Hz, 1 H), 6.86e6.74 (m, 1 H),
4.00 (t, J ¼ 6.8 Hz, 2 H), 1.66e1.57 (m, 2 H), 0.92 (t, J ¼ 7.6 Hz, 3 H).
HR-MS (ESI): m/z [M ꢀ H]- calcd for C10H10F2NO3: 230.0623; found:
230.0623.
General procedure for the synthesis of compounds 1aev. To a
solution of phenol A1e19 (1 mmol), alcohol B1e4 (1.35 mmol),
PPh3 (1.5 mmol) in anhydrous THF (5 mL) at 0 ꢁC was added
dropwise a solution of DIAD (1.5 mmol) in anhydrous THF (0.3 mL).
The reaction mixture was stirred at 0 ꢁC for 30 min and allowed to
warm to room temperature. After the reaction was completed, the
reaction mixture was purified by column chromatography (10e25%
EtOAc in PE) to give the desired product 1aꢀv.
Propyl (3,5-dichloro-2-hydroxyphenyl)carbamate (A17). Com-
pound A17 was prepared from 2-amino-3,5-dichlorophenol
following the preparation method of A1. Flash column chroma-
tography was performed eluting the column with 5% EtOAc in PE.
Orange solid (365 mg, 25%). 1H NMR (400 MHz, DMSO-d6)
d: 9.90 (s,
1 H), 8.80 (brs, 1 H), 7.61 (d, J ¼ 2.0 Hz, 1 H), 7.23 (d, J ¼ 2.8 Hz, 1 H),
4.04 (t, J ¼ 6.8 Hz, 2 H), 1.68e1.59 (m, 2 H), 0.92 (t, J ¼ 7.6 Hz, 3 H).
HR-MS (ESI): m/z [M ꢀ H]- calcd for C10H10Cl2NO3: 262.0032;
found: 262.0036.
Propyl (2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)methoxy)
phenyl)carbamate (1a). White solid (7.6 g, 71%). 1H NMR (400 MHz,
CDCl3)
d
: 8.09 (d, J ¼ 6.0 Hz, 1 H), 7.50e7.42 (m, 6 H), 7.34e7.21 (m,
9 H), 7.18 (s, 1 H), 7.00e6.89 (m, 2 H), 6.72 (dd, J ¼ 1.6, 7.6 Hz, 1 H),
4.18e4.08 (m, 3 H), 3.84 (dd, J ¼ 6.8, 11.2 Hz, 1 H), 3.48 (dd, J ¼ 5.6,
10.8 Hz, 1 H), 3.42e3.39 (m, 1 H), 3.34 (q, J ¼ 5.2 Hz, 1 H), 3.16 (dd,
tert-Butyl
3-hydroxy-4-((propoxycarbonyl)amino)benzoate
(A18). Compound A18 was prepared from tert-butyl 3-hydroxy-4-
nitrobenzoate following the preparation method of A7. Flash col-
umn chromatography was performed eluting the column with 10%
J ¼ 5.2, 10.8 Hz, 1 H), 1.75e1.66 (m, 2 H), 0.97 (t, J ¼ 7.6 Hz, 3 H). 13
C
NMR (100 MHz, acetone-d6) d: 154.2, 148.0, 144.7, 129.4, 129.2,
7

H. Zhao, S. Li, S. Cheng et al.
Tetrahedron 93 (2021) 132304
128.7, 128.0, 123.5, 122.0, 119.5, 112.8, 87.8, 68.4, 67.0, 63.1, 55.1,
54.5, 23.0,10.5. HR-MS (ESI): m/z [M þ Na]þ calcd for C33H33NNaO5:
546.2251; found: 546.2226.
(s, 3 H), 1.73e1.66 (m, 2 H), 0.97 (t, J ¼ 7.5 Hz, 3 H). 13C NMR
(125 MHz, CDCl3) d: 153.6, 144.2, 143.4, 131.3, 128.5, 127.9, 127.6,
127.2, 122.7, 119.0, 111.2, 87.1, 67.3, 66.7, 61.9, 54.5, 54.2, 22.3, 21.0,
10.4. HR-MS (ESI): m/z [M þ Na]þ calcd for C34H35NNaO5: 560.2407;
found: 560.2397.
Isopropyl
methoxy)phenyl)carbamate (1b). White solid (1.1 g, 70%).1H NMR
(400 MHz, CDCl3)
(2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)
d: 8.10 (d, J ¼ 7.2 Hz, 1 H), 7.50e7.42 (m, 6 H),
Propyl (4-methyl-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-
7.35e7.20 (m, 9 H), 7.12 (s, 1 H), 6.98e6.90 (m, 2 H), 6.72 (dd, J ¼ 1.6,
7.6 Hz, 1 H), 5.05e4.99 (m, 1 H), 4.15 (dd, J ¼ 3.2, 11.2 Hz, 1 H), 3.84
(dd, J ¼ 7.2, 11.6 Hz, 1 H), 3.49 (dd, J ¼ 5.6, 10.8 Hz, 1 H), 3.43e3.39
(m, 1 H), 3.34 (q, J ¼ 5.2 Hz, 1 H), 3.17 (dd, J ¼ 5.2, 10.4 Hz, 1 H), 1.31
(d, J ¼ 1.6 Hz, 3 H), 1.29 (d, J ¼ 1.2 Hz, 3 H). 13C NMR (100 MHz,
yl)methoxy)phenyl)carbamate (1h). White solid (1.37 g, 85%). 1H
NMR (500 MHz, CDCl3)
d: 7.95 (brs, 1 H), 7.49e7.43 (m, 6 H),
7.32e7.29 (m, 6 H), 7.26e7.23 (m, 3 H), 7.08 (brs, 1 H), 6.77 (d,
J ¼ 8.0 Hz, 1 H), 6.52 (d, J ¼ 1.0 Hz, 1 H), 4.14e4.08 (m, 3 H), 3.81 (dd,
J ¼ 7.0, 11.0 Hz, 1 H), 3.48 (dd, J ¼ 5.5, 10.5 Hz, 1 H), 3.43e3.38 (m,
1 H), 3.34 (q, J ¼ 5.0 Hz, 1 H), 3.17 (dd, J ¼ 5.5, 11.0 Hz, 1 H), 2.28 (s,
3 H), 1.73e1.66 (m, 2 H), 0.97 (t, J ¼ 7.5 Hz, 3 H). 13C NMR (125 MHz,
acetone-d6) d: 153.7, 147.8, 144.7, 129.4, 129.2, 128.7, 128.0, 123.4,
122.0, 119.3, 112.7, 87.7, 68.8, 68.3, 63.1, 55.1, 54.5, 22.23, 22.22. HR-
MS (ESI): m/z [M þ Na]þ calcd for C33H33NNaO5: 546.2251; found:
546.2247.
acetone-d6) d: 154.2, 148.0, 144.7, 133.2, 129.4, 128.7, 128.0, 126.5,
122.3, 119.5, 113.5, 87.7, 68.3, 66.9, 63.0, 55.1, 54.5, 23.0, 21.1, 10.6.
HR-MS (ESI): m/z [M þ Na]þ calcd for C34H35NNaO5: 560.2407;
found: 560.2380.
tert-Butyl
methoxy)phenyl)carbamate (1c). White solid (2.5 g, 79%). 1H NMR
(400 MHz, CDCl3)
(2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)
d
: 8.08 (d, J ¼ 7.6 Hz, 1 H), 7.50e7.17 (m, 15 H),
Propyl (5-methoxy-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-
7.04 (brs, 1 H), 6.99e6.85 (m, 2 H), 6.71 (dd, J ¼ 1.2, 7.6 Hz, 1 H), 4.15
(dd, J ¼ 3.2, 11.2 Hz, 1 H), 3.83 (dd, J ¼ 6.8, 11.2 Hz, 1 H), 3.48 (dd,
J ¼ 5.6, 10.8 Hz, 1 H), 3.45e3.38 (m, 1 H), 3.38e3.29 (m, 1 H), 3.17
(dd, J ¼ 5.2, 10.8 Hz, 1 H), 1.52 (s, 9 H). 13C NMR (125 MHz, acetone-
yl)methoxy)phenyl)carbamate (1i). Colorless oil (1.4 g, 84%). 1H
NMR (500 MHz, CDCl3) d: 7.84 (s, 1 H), 7.51e7.44 (m, 6 H), 7.32e7.34
(m,6 H), 7.30e7.23 (m, 4 H), 6.68 (d, J ¼ 9.0 Hz,1 H), 6.48 (dd, J ¼ 3.0,
8.5 Hz, 1 H), 4.17e4.10 (m, 3 H), 3.83e3.77 (m, 4 H), 3.49 (dd, J ¼ 6.0,
10.5 Hz, 1 H), 3.43e3.38 (m, 1 H), 3.36 (q, J ¼ 5.0 Hz, 1 H), 3.17 (dd,
d6) d: 153.3, 147.7, 144.7, 129.4, 129.3, 128.7, 128.0, 123.2, 121.9, 119.2,
112.5, 87.7, 80.3, 68.2, 63.0, 55.0, 54.5, 28.4. HR-MS (ESI): m/z [M þ
J ¼ 5.0, 10.5 Hz, 1 H), 1.75e1.70 (m, 2 H), 1.00 (t, J ¼ 7.5 Hz, 3 H). 13
C
Na]þ calcd for C34H35NNaO5: 560.2407; found: 560.2425.
NMR (125 MHz, CDCl3) d: 154.5, 153.5, 143.4, 140.4, 129.7, 128.9,
Propyl (2-(((2S,3R)-3-((trityloxy)methyl)oxiran-2-yl)methoxy)
phenyl)carbamate (1d). White solid (350 mg, 87%). 1H NMR
128.5, 127.9, 127.2, 112.6, 107.4, 87.1, 67.9, 66.8, 61.9, 55.7, 54.6, 54.2,
22.2, 10.3. HR-MS (ESI): m/z [M þ Na]þ calcd for C34H35NNaO6:
576.2357; found: 576.2344.
(400 MHz, CDCl3)
d
: 8.09 (d, J ¼ 6.4 Hz, 1 H), 7.48e7.42 (m, 6 H),
7.34e7.21 (m, 9 H), 7.18 (s, 1 H), 7.00e6.90 (m, 2 H), 6.72 (dd, J ¼ 2.0,
8.0 Hz, 1 H), 4.17e4.08 (m, 3 H), 3.85 (dd, J ¼ 6.8, 11.2 Hz, 1 H), 3.48
(dd, J ¼ 5.6,10.8 Hz,1 H), 3.43e3.38 (m,1 H), 3.34 (q, J ¼ 5.2 Hz,1 H),
3.16 (dd, J ¼ 5.6, 10.8 Hz, 1 H), 1.75e1.66 (m, 2 H), 0.98 (t, J ¼ 7.2 Hz,
Propyl (4-methoxy-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-
yl)methoxy)phenyl)carbamate (1j). Pale-yellow solid (1.45 g,
87%). 1H NMR (500 MHz, CDCl3)
d: 7.96 (brs, 1 H), 7.48e7.43 (m,
6 H), 7.34e7.27 (m, 6 H), 7.27e7.20 (m, 3 H), 6.93 (brs, 1 H), 6.48 (dd,
J ¼ 2.5, 9.0 Hz, 1 H), 6.34 (d, J ¼ 2.5 Hz, 1 H), 4.15e4.06 (m, 3 H),
3.82e3.73 (m, 4 H), 3.47 (dd, J ¼ 5.5, 10.5 Hz, 1 H), 3.41e3.38 (m,
1 H), 3.34 (q, J ¼ 5.0 Hz,1 H), 3.15 (dd, J ¼ 5.0,10.5 Hz,1 H),1.72e1.65
3 H). 13C NMR (100 MHz, acetone-d6)
d: 154.2, 148.0, 144.7, 129.4,
129.1, 128.7, 128.0, 123.5, 122.0, 119.5, 112.8, 87.7, 68.4, 66.97, 63.1,
55.1, 54.5, 23.0, 10.5. HR-MS (ESI): m/z [M þ Na]þ calcd for
C
33H33NNaO5: 546.2251; found: 546.2229.
(m, 2 H), 0.97 (t, J ¼ 7.5 Hz, 3 H). 13C NMR (125 MHz, acetone-d6)
d:
Propyl (2-(((2S,3S)-3-((trityloxy)methyl)oxiran-2-yl)methoxy)
156.9, 154.5, 149.5, 144.7, 129.4, 128.7, 128.0, 122.2, 121.0, 105.5,
100.7, 87.7, 68.4, 66.8, 63.1, 55.7, 55.1, 54.5, 23.0, 10.6. HR-MS (ESI):
m/z [M þ Na]þ calcd for C34H35NNaO6: 576.2357; found: 576.2338.
Propyl (2-bromo-6-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)
methoxy)phenyl)carbamate (1k). White solid (1.31 g, 72%). 1H NMR
phenyl)carbamate (1e). White solid (475 mg, 91%). 1H NMR
(500 MHz, CDCl3) d: 8.11 (brs, 1 H), 7.49e7.42 (m, 6 H), 7.33e7.30
(m, 6 H), 7.27e7.22 (m, 4 H), 7.00e6.94 (m, 2 H), 6.85 (dd, J ¼ 1.5,
7.5 Hz, 1 H), 4.31 (dd, J ¼ 2.5, 11.5 Hz, 1 H), 4.13 (t, J ¼ 7.0 Hz, 2 H),
3.97 (dd, J ¼ 6.0, 11.5 Hz, 1 H), 3.40 (dd, J ¼ 3.5, 10.5 Hz, 1 H),
3.35e3.31 (m,1 H), 3.25 (dd, J ¼ 5.0,11.0 Hz,1 H), 3.18e3.16 (m,1 H),
1.74e1.67 (m, 2 H), 0.98 (t, J ¼ 7.5 Hz, 3 H). 13C NMR (125 MHz,
(500 MHz, CDCl3)
d: 7.47e7.43 (m, 6 H), 7.32e7.29 (m, 6 H),
7.27e7.20 (m, 4 H), 7.03 (t, J ¼ 8.5 Hz, 1 H), 6.75 (d, J ¼ 8.0 Hz, 1 H),
6.02 (s, 1 H), 4.12e4.06 (m, 3 H), 3.88 (dd, J ¼ 6.0, 11.0 Hz, 1 H), 3.44
(dd, J ¼ 6.0, 11.0 Hz, 1 H), 3.37e3.35 (m, 1 H), 3.31 (q, J ¼ 5.5 Hz, 1 H),
3.16 (dd, J ¼ 5.0, 10.5 Hz, 1 H), 1.70e1.63 (m, 2 H), 0.93 (t, J ¼ 7.5 Hz,
CDCl3) d: 153.6, 146.4, 143.6, 128.6, 128.1, 127.9, 127.1, 122.6, 121.9,
118.5, 111.6, 86.9, 69.1, 66.8, 63.5, 54.9, 53.7, 22.2, 10.4. HR-MS (ESI):
m/z [M þ Na]þ calcd for C33H33NNaO5: 546.2251; found: 546.2233.
3 H). 13C NMR (125 MHz, CDCl3)
d: 154.9, 154.3, 143.5, 128.5, 128.3,
Propyl
(2-(((2R,3R)-3-((trityloxy)methyl)oxiran-2-yl)
127.9,127.2,125.4,125.3,123.3,112.0, 87.0, 67.5, 67.2, 61.9, 54.5, 54.1,
22.3, 10.3. HR-MS (ESI): m/z [M þ Na]þ calcd for C33H32BrNNaO5:
624.1356; found: 624.1333.
methoxy)phenyl)carbamate (1f). White solid (349 mg, 95%). 1H
NMR (500 MHz, CDCl3) : 8.11 (brs, 1 H), 7.49e7.42 (m, 6 H),
d
7.33e7.28 (m, 6 H), 7.27e7.23 (m, 4 H), 7.01e6.92 (m, 2 H), 6.85 (dd,
J ¼ 2.0, 7.5 Hz, 1 H), 4.31 (dd, J ¼ 2.5, 11.5 Hz, 1 H), 4.12 (t, J ¼ 6.5 Hz,
2 H), 3.97 (dd, J ¼ 6.0, 11.5 Hz, 1 H), 3.40 (dd, J ¼ 3.0, 11.0 Hz, 1 H),
3.33e3.31 (m,1 H), 3.25 (dd, J ¼ 5.0,11.0 Hz,1 H), 3.18e3.16 (m,1 H),
1.74e1.67 (m, 2 H), 0.97 (t, J ¼ 7.5 Hz, 3 H). 13C NMR (125 MHz,
Propyl (5-bromo-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)
methoxy)phenyl)carbamate (1l). White solid (1.8 g, 82%). 1H NMR
(400 MHz, CDCl3) d: 8.30 (brs, 1 H), 7.47e7.42 (s, 6 H), 7.35e7.22 (m,
9 H), 7.15 (brs, 1 H), 7.02 (dd, J ¼ 2.4, 8.4 Hz, 1 H), 6.57 (d, J ¼ 8.8 Hz,
1 H), 4.19e4.08 (m, 3 H), 3.80 (dd, J ¼ 6.8, 11.2 Hz, 1 H), 3.50 (dd,
J ¼ 5.2, 10.4 Hz, 1 H), 3.41e3.30 (m, 2 H), 3.15 (dd, J ¼ 5.6, 10.8 Hz,
1 H), 1.75e1.66 (m, 2 H), 0.98 (t, J ¼ 7.2 Hz, 3 H). 13C NMR (100 MHz,
CDCl3) d: 153.6, 146.4, 143.6, 128.6, 128.1, 127.9, 127.1, 122.6, 121.9,
118.5, 111.6, 86.9, 69.1, 66.8, 63.5, 54.9, 53.7, 22.2, 10.4. HR-MS (ESI):
m/z [M þ Na]þ calcd for C33H33NNaO5: 546.2251; found: 546.2240.
Propyl (5-methyl-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-
yl)methoxy)phenyl)carbamate (1g). White solid (1.47 g, 91%). 1H
CDCl3) d: 153.2, 145.3, 143.4, 129.2, 128.5, 128.0, 127.3, 125.0, 121.1,
114.2, 112.5, 87.1, 67.5, 67.1, 61.8, 54.5, 54.0, 22.2, 10.3. HR-MS (ESI):
m/z [M
624.1326.
þ
Na]þ calcd for C33H32BrNNaO5: 624.1356; found:
NMR (500 MHz, CDCl3)
d: 7.94 (brs, 1 H), 7.47e7.43 (m, 6 H),
7.31e7.28 (m, 6 H), 7.27e7.22 (m, 3 H), 7.15 (brs, 1 H), 6.72 (dd,
J ¼ 1.5, 8.5 Hz, 1 H), 6.61 (d, J ¼ 8.5 Hz, 1 H), 4.14e4.08 (m, 3 H), 3.80
(dd, J ¼ 6.5, 11.0 Hz, 1 H), 3.46 (dd, J ¼ 5.5, 10.5 Hz, 1 H), 3.40e3.37
(m, 1 H), 3.33 (q, J ¼ 5.5 Hz, 1 H), 3.15 (dd, J ¼ 5.5, 10.5 Hz, 1 H), 2.28
Propyl (4-bromo-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)
methoxy)phenyl)carbamate (1 m). White solid (1.7 g, 77%). 1H NMR
(400 MHz, CDCl3)
d: 7.99 (d, J ¼ 8.8 Hz, 1 H), 7.48e7.42 (m, 6 H),
7.35e7.23 (m, 9 H), 7.10e7.08 (m, 2 H), 6.81 (d, J ¼ 2.0 Hz, 1 H),
8

H. Zhao, S. Li, S. Cheng et al.
Tetrahedron 93 (2021) 132304
4.15e4.08 (m, 3 H), 3.72 (dd, J ¼ 7.2, 11.2 Hz, 1 H), 3.55 (dd, J ¼ 5.2,
10.8 Hz, 1 H), 3.42e3.33 (m, 2 H), 3.12 (dd, J ¼ 5.6, 10.4 Hz, 1 H),
1.76e1.64 (m, 2 H), 0.97 (t, J ¼ 7.6 Hz, 3 H). 13C NMR (100 MHz,
2-yl)methoxy)phenyl)carbamate (1s). Colorless oil (720 mg, 86%).
1H NMR (400 MHz, CDCl3)
d: 7.81 (brs, 1 H), 7.45e7.38 (m, 6 H),
7.33e7.15 (m, 10 H), 6.89e6.82 (m, 1 H), 4.38e4.34 (m, 1 H), 4.10 (t,
J ¼ 6.8 Hz, 2 H), 3.84e3.79 (m, 1 H), 3.46e3.30 (m, 3 H), 3.11 (dd,
CDCl3) d: 153.4, 146.9, 143.4, 128.5, 128.0, 127.3, 127.1, 124.5, 119.5,
114.6, 114.5, 87.1, 67.6, 67.0, 61.6, 54.4, 53.9, 22.2, 10.4. HR-MS (ESI):
J ¼ 4.8, 10.4 Hz, 1 H), 1.74e1.63 (m, 2 H), 0.96 (t, J ¼ 7.6 Hz, 3 H). 13
C
m/z [M
624.1327.
þ
Na]þ calcd for C33H32BrNNaO5: 624.1356; found:
NMR (100 MHz, CDCl3)
d
: 153.6, 146.6 (dd, J ¼ 11.0, 243.0 Hz), 143.7
(dd, J ¼ 14.0, 245.0 Hz), 143.4, 136.0 (d, J ¼ 9.0 Hz), 128.5, 127.9,
127.2, 112.9 (d, J ¼ 5.0 Hz), 111.3 (d, J ¼ 17.0 Hz), 87.1, 72.7, 67.1, 61.8,
55.0, 54.0, 22.2, 10.3. HR-MS (ESI): m/z [M þ Na]þ calcd for
Propyl (3-bromo-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)
methoxy)phenyl)carbamate (1n). White solid (1.3 g, 72%). 1H NMR
(500 MHz, CDCl3)
d
: 8.09 (d, J ¼ 8.0 Hz, 1 H), 7.48 (s, 1 H), 7.44e7.38
C
33H31F2NNaO5: 582.2063; found: 582.2053.
(m, 6 H), 7.29e7.24 (m, 6 H), 7.23e7.18 (m, 3 H), 7.14 (dd, J ¼ 1.5,
8.0 Hz, 1 H), 6.96 (t, J ¼ 8.0 Hz, 1 H), 4.31 (dd, J ¼ 3.5, 11.5 Hz, 1 H),
4.11 (t, J ¼ 7.0 Hz, 2 H), 3.56 (dd, J ¼ 7.5, 11.0 Hz, 1 H), 3.46e3.40 (m,
2 H), 3.38e3.34 (m,1 H), 3.12 (dd, J ¼ 4.5,10.5 Hz,1 H),1.71e1.64 (m,
Propyl (3,5-dichloro-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-
2-yl)methoxy)phenyl)carbamate (1t). Colorless oil (368 mg, 49%).
1H NMR (400 MHz, CDCl3)
d
: 8.14 (d, J ¼ 2.0 Hz, 1 H), 7.52 (brs, 1 H),
7.46e7.37 (m, 6 H), 7.33e7.18 (m, 9 H), 6.98 (d, J ¼ 2.8 Hz, 1 H), 4.31
(dd, J ¼ 2.8, 11.2 Hz, 1 H), 4.11 (t, J ¼ 6.8 Hz, 2 H), 3.55 (dd, J ¼ 7.2,
11.2 Hz, 1 H), 3.45 (dd, J ¼ 6.0, 10.8 Hz, 1 H), 3.41e3.33 (m, 2 H), 3.10
(dd, J ¼ 4.8, 10.8 Hz, 1 H), 1.73e1.64 (m, 2 H), 0.95 (t, J ¼ 7.6 Hz, 3 H).
2 H), 0.95 (t, J ¼ 7.5 Hz, 3 H). 13C NMR (125 MHz, CDCl3)
d: 153.5,
144.0, 143.4, 133.6, 128.5, 127.9, 127.2, 126.5, 126.1, 118.1, 116.2, 87.0,
71.6, 67.0, 61.8, 55.5, 54.0, 22.2, 10.3. HR-MS (ESI): m/z [M þ Na]þ
calcd for C33H32BrNNaO5: 624.1356; found: 624.1329.
13C NMR (100 MHz, CDCl3)
d: 153.2, 143.4, 141.6, 134.2, 130.5, 128.5,
Propyl (5-fluoro-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)
127.9, 127.5, 127.2, 123.0, 117.4, 87.1, 71.9, 67.2, 61.7, 55.5, 53.9, 22.2,
10.3. HR-MS (ESI): m/z [M þ Na]þ calcd for C33H31Cl2NNaO5:
614.1471; found: 614.1461.
tert-Butyl 4-((propoxycarbonyl)amino)-3-(((2R,3S)-3-((trity-
loxy)methyl)oxiran-2-yl)methoxy)benzoate (1u). White solid
methoxy)phenyl)carbamate (1o). White solid (1.39 g, 86%). 1H
NMR (500 MHz, CDCl3)
d
: 7.93 (d, J ¼ 6.5 Hz, 1 H), 7.49e7.41 (m,
6 H), 7.32e7.28 (m, 6 H), 7.27e7.21 (m, 4 H), 6.66e6.56 (m, 2 H),
4.15e4.11 (m, 3 H), 3.80 (dd, J ¼ 6.5, 11.0 Hz, 1 H), 3.48 (dd, J ¼ 5.5,
11.0 Hz, 1 H), 3.40e3.37 (m, 1 H), 3.35 (q, J ¼ 5.0 Hz, 1 H), 3.15 (dd,
(510 mg, 82%). 1H NMR (500 MHz, CDCl3)
d
: 8.16 (d, J ¼ 8.0 Hz, 1 H),
J ¼ 5.5, 10.5 Hz, 1 H), 1.74e1.67 (m, 2 H), 0.98 (t, J ¼ 7.5 Hz, 3 H). 13
C
7.63 (dd, J ¼ 1.5, 8.5 Hz, 1 H), 7.48e7.43 (m, 6 H), 7.38e7.35 (m, 2 H),
7.33e7.29 (m, 6 H), 7.27e7.21 (m, 3 H), 4.22 (dd, J ¼ 3.5,11.0 Hz,1 H),
4.16e4.11 (m, 2 H), 3.84 (dd, J ¼ 7.5, 11.0 Hz, 1 H), 3.49 (dd, J ¼ 6.0,
11.0 Hz, 1 H), 3.45e3.41 (m, 1 H), 3.35 (q, J ¼ 5.0 Hz, 1 H), 3.17 (dd,
J ¼ 5.0, 10.5 Hz, 1 H), 1.75e1.68 (m, 2 H), 1.57 (s, 9 H), 0.98 (t,
NMR (125 MHz, CDCl3)
d
: 157.6 (d, J ¼ 236.3 Hz), 153.3, 143.4, 142.3
(d, J ¼ 2.5 Hz), 129.1 (d, J ¼ 11.3 Hz), 128.5, 128.0, 127.3, 111.9 (d,
J ¼ 8.8 Hz), 107.9 (d, J ¼ 23.8 Hz), 106.1 (d, J ¼ 28.8 Hz), 87.1, 67.9,
67.0, 61.8, 54.6, 54.1, 22.2,10.3. HR-MS (ESI): m/z [M þ Na]þ calcd for
C
33H32FNNaO5: 564.2157; found: 564.2140.
J ¼ 7.5 Hz, 3 H). 13C NMR (125 MHz, CDCl3)
d: 165.4, 153.2, 145.6,
Propyl (4-fluoro-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)
143.4, 131.9, 128.5, 128.0, 127.2, 125.9, 123.7, 117.0, 111.6, 87.1, 80.9,
67.4, 67.1, 61.9, 54.6, 53.8, 28.2, 22.2, 10.4. HR-MS (ESI): m/z [M þ
Na]þ calcd for C38H41NNaO7: 646.2775; found: 646.2760.
methoxy)phenyl)carbamate (1p). White solid (1.27 g, 78%). 1H
NMR (500 MHz, CDCl3) d: 8.02 (s, 1 H), 7.51e7.42 (m, 6 H), 7.33e7.30
(m, 6 H), 7.30e7.22 (m, 3 H), 7.00 (s, 1 H), 6.69e6.65 (m, 1 H), 6.47
(dd, J ¼ 3.0, 10.0 Hz, 1 H), 4.14e4.10 (m, 3 H), 3.76 (dd, J ¼ 7.0,
11.0 Hz, 1 H), 3.53 (dd, J ¼ 5.5, 10.5 Hz, 1 H), 3.41e3.34 (m, 2 H), 3.14
(dd, J ¼ 5.5, 11.0 Hz, 1 H), 1.73e1.66 (m, 2 H), 0.97 (t, J ¼ 7.5 Hz, 3 H).
Propyl
oxiran-2-yl)methoxy)phenyl)carbamate (1v). White solid (2.8 g,
88%). 1H NMR (400 MHz, CDCl3)
: 7.89 (s, 1 H), 7.50e7.41 (m, 6 H),
(4-(piperidin-1-yl)-2-(((2R,3S)-3-((trityloxy)methyl)
d
7.34e7.22 (m, 9 H), 6.91 (s, 1 H), 6.54 (dd, J ¼ 2.0, 9.2 Hz, 1 H), 6.40
(d, J ¼ 2.0 Hz,1 H), 4.20e4.04 (m, 3 H), 3.83 (dd, J ¼ 6.8,11.8 Hz,1 H),
3.47e3.31 (m, 3 H), 3.17 (dd, J ¼ 5.2, 10.8 Hz, 1 H), 3.02 (t, J ¼ 5.2 Hz,
4 H), 1.73e1.66 (m, 6 H), 1.58e1.55 (m, 2 H), 0.96 (t, J ¼ 7.6 Hz, 3 H).
13C NMR (125 MHz, acetone-d6)
d
: 159.3 (d, J ¼ 238.8 Hz), 154.4,
149.3 (d, J ¼ 7.5 Hz), 144.7, 129.4, 128.7, 128.0, 125.3 (d, J ¼ 2.5 Hz),
120.7, 107.4 (d, J ¼ 22.5 Hz), 101.1 (d, J ¼ 27.5 Hz), 87.7, 68.8, 67.0,
63.0, 55.1, 54.3, 22.9, 10.5. HR-MS (ESI): m/z [M þ Na]þ calcd for
13C NMR (100 MHz, CDCl3)
d: 153.8, 148.8, 147.3, 143.5, 128.5, 128.0,
C
33H32FNNaO5: 564.2157; found: 564.2140.
127.2, 120.5, 119.4, 109.6, 102.1, 87.1, 67.2, 66.6, 61.9, 54.6, 54.2, 51.6,
Propyl (5-nitro-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)
26.0, 24.2, 22.3, 10.4. HR-MS (ESI): m/z [M þ H]þ calcd for
methoxy)phenyl)carbamate (1q). Yellow solid (1.25 g, 74%). 1H
C38H43N2O5: 607.3166; found: 607.3152.
NMR (500 MHz, CDCl3)
d
: 9.03 (s, 1 H), 7.86 (dd, J ¼ 2.5, 9.0 Hz, 1 H),
7.48e7.42 (m, 6 H), 7.33e7.30 (m, 6 H), 7.27e7.23 (m, 4 H), 6.77 (d,
J ¼ 9.0 Hz, 1 H), 4.31 (dd, J ¼ 3.0, 11.5 Hz, 1 H), 4.20e4.13 (m, 2 H),
3.95 (dd, J ¼ 7.5, 11.5 Hz, 1 H), 3.56 (dd, J ¼ 5.0, 10.5 Hz, 1 H),
3.45e3.40 (m, 1 H), 3.36 (q, J ¼ 5.5 Hz, 1 H), 3.19 (dd, J ¼ 5.5, 10.5 Hz,
1 H), 1.76e1.69 (m, 2 H), 0.99 (t, J ¼ 7.5 Hz, 3 H). 13C NMR (125 MHz,
4.4. Preparation of target compounds 2aek
General procedure for the synthesis of target compounds. To
a solution of 1 (1.0 equiv.) in anhydrous THF (5 mL) under argon was
added KOH (2.5 equiv.). The reaction mixture was stirred at room
temperature for 3.5e44 h. Water (10 mL) and brine (10 mL) was
added, the mixture was extracted with EtOAc (15 mL ꢂ 3). The
combined organic layer was washed with brine, dried over anhy-
drous Na2SO4, filtered and evaporated in vacuum. The residue was
purified by column chromatography eluting with 10e20% EtOAc in
PE or triturated to give the corresponding products 2aek.
CDCl3) d: 153.1, 150.7, 143.3, 142.1, 128.5, 128.3, 128.0, 127.3, 118.6,
113.6, 110.3, 87.2, 68.1, 67.4, 61.7, 54.5, 53.7, 22.2, 10.3. HR-MS (ESI):
m/z [M þ Na]þ calcd for C33H32N2NaO7: 591.2102; found: 591.2078.
Propyl (4-nitro-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)
methoxy)phenyl)carbamate (1r). Yellow solid (1.2 g, 71%). 1H NMR
(500 MHz, CDCl3)
d
: 8.31 (d, J ¼ 9.0 Hz, 1 H), 7.93 (dd, J ¼ 2.5, 9.0 Hz,
1 H), 7.59 (d, J ¼ 2.5 Hz, 1 H), 7.46 (d, J ¼ 7.5 Hz, 7 H), 7.34e7.24 (m,
9 H), 4.29 (dd, J ¼ 2.5, 11.0 Hz, 1 H), 4.20e4.12 (m, 2 H), 3.83 (dd,
J ¼ 7.5, 11.0 Hz, 1 H), 3.59 (dd, J ¼ 5.5, 10.5 Hz, 1 H), 3.46e3.43 (m,
1 H), 3.37 (q, J ¼ 5.0 Hz,1 H), 3.16 (dd, J ¼ 5.5, 11.0 Hz,1 H), 1.76e1.69
(R)-1-((S)-3,4-Dihydro-2H-benzo[b][1,4]oxazin-3-yl)-2-(trity-
loxy)ethan-1-ol (2a).White solid (156 mg, 94%); mp: 55ꢀ57 ꢁC. The
product was analyzed by chiral HPLC (IC, 5
eluent: hexane/isopropanol, 95/5; flow rate: 1.0 mL/min;
m
m, 4.6 mm ꢂ 250 mm;
(m, 2 H), 0.99 (t, J ¼ 7.5 Hz, 3 H). 13C NMR (125 MHz, CDCl3)
d: 152.9,
l
¼ 220 nm; T ¼ 15 ꢁC): tR ¼ 10.02 min (99.32%), 14.57 min (0.68%).
145.6, 143.3, 142.2, 134.3, 128.5, 128.0, 127.3, 118.3, 116.8, 106.2, 87.2,
68.0, 67.5, 61.6, 54.4, 53.7, 22.1, 10.3. HR-MS (ESI): m/z [M þ Na]þ
calcd for C33H32N2NaO7: 591.2102; found: 591.2075.
The enantiomeric purity of 2a was determined to be 98% ee.
20
[
a
]
¼ þ3.2 (c 1, EtOAc). 1H NMR (400 MHz, acetone-d6):
D
d
7.54e7.51 (m, 6 H), 7.38e7.31 (m, 6 H), 7.30e7.24 (m, 3 H),
Propyl (3,4-difluoro-2-(((2R,3S)-3-((trityloxy)methyl)oxiran-
6.69e6.59 (m, 3 H), 6.53e6.48 (m, 1 H), 4.97 (brs, 1 H), 4.37 (d,
9

H. Zhao, S. Li, S. Cheng et al.
Tetrahedron 93 (2021) 132304
J ¼ 6.0 Hz, 1 H), 4.11e4.08 (m, 1 H), 3.86 (dd, J ¼ 6.8, 10.8 Hz, 1 H),
3.81e3.76 (m, 1 H), 3.56e3.52 (m, 1 H), 3.36 (dd, J ¼ 4.0, 10.0 Hz,
1 H), 3.20 (dd, J ¼ 4.8, 10.0 Hz, 1 H). 13C NMR (100 MHz, acetone-d6):
2.12 (s, 3 H). 13C NMR (125 MHz, acetone-d6):
d 145.0, 142.4, 134.5,
130.9, 129.5, 128.6, 127.9, 118.8, 116.7, 116.5, 87.4, 71.0, 66.7, 66.5,
53.3, 20.8. HR-MS (ESI): m/z [M þ Na]þ calcd for C30H29NNaO3:
474.2040; found: 474.2025.
(R)-1-((S)-7-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-
yl)-2-(trityloxy)ethan-1-ol (2f). Off-white solid (157 mg, 87%); mp:
d
145.0, 144.6, 134.9, 129.6, 128.7, 127.9, 122.0, 118.4, 116.8, 116.3,
87.5, 71.1, 66.9, 66.6, 53.3. HR-MS (ESI): m/z [M þ Na]þ calcd for
C
29H27NNaO3: 460.1883; found: 460.1866.
(S)-1-((R)-3,4-Dihydro-2H-benzo[b][1,4]oxazin-3-yl)-2-(trity-
58ꢀ60 ꢁC. The product was analyzed by chiral HPLC (IC, 5
mm,
loxy)ethan-1-ol (2b).White solid (135 mg, 77%); mp: 50ꢀ52 ꢁC. The
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 95/5; flow rate:
product was analyzed by chiral HPLC (IC, 5
eluent: hexane/isopropanol, 95/5; flow rate: 1.0 mL/min;
m
m, 4.6 mm ꢂ 250 mm;
1.0 mL/min;
l
¼ 220 nm; T ¼ 15 ꢁC): tR ¼ 10.02 min (97.78%),
16.75 min (2.22%). The enantiomeric purity of 2f was determined to
22
l
¼ 220 nm; T ¼ 15 ꢁC): tR ¼ 10.06 min (1.34%), 14.52 min (98.66%).
be 96% ee. [
a]
¼ þ6.8 (c 1, EtOAc). 1H NMR (500 MHz, acetone-d6):
D
The enantiomeric purity of 2b was determined to be 97% ee.
d 7.55e7.51 (m, 6 H), 7.36e7.31 (m, 6 H), 7.29e7.24 (m, 3 H),
22
[
a
]
¼ ꢀ4.7 (c 1, EtOAc). 1H NMR (400 MHz, acetone-d6):
6.54e6.45 (m, 3 H), 4.78 (brs, 1 H), 4.37 (d, J ¼ 6.0 Hz, 1 H), 4.08 (dd,
J ¼ 3.0, 10.5 Hz, 1 H), 3.85 (dd, J ¼ 7.0, 10.5 Hz, 1 H), 3.80e3.75 (m,
1 H), 3.52e3.48 (m, 1 H), 3.35 (dd, J ¼ 4.0, 10.0 Hz, 1 H), 3.18 (dd,
J ¼ 4.5, 10.0 Hz, 1 H), 2.13 (s, 3 H). 13C NMR (125 MHz, acetone-d6):
D
d
7.56e7.49 (m, 6 H), 7.38e7.31 (m, 6 H), 7.30e7.23 (m, 3 H),
6.69e6.59 (m, 3 H), 6.52e6.48 (m, 1 H), 4.97 (brs, 1 H), 4.38 (d,
J ¼ 6.0 Hz, 1 H), 4.09 (dd, J ¼ 3.2, 10.8 Hz, 1 H), 3.86 (dd, J ¼ 6.8,
10.8 Hz, 1 H), 3.81e3.76 (m, 1 H), 3.56e3.52 (m, 1 H), 3.36 (dd,
J ¼ 4.0, 9.6 Hz,1 H), 3.20 (dd, J ¼ 4.8, 9.6 Hz,1 H). 13C NMR (100 MHz,
d
144.2, 143.7, 131.4, 128.7, 127.8, 127.0, 126.9, 121.5, 116.5, 115.6,
86.6, 70.1, 66.1, 65.7, 52.5, 19.7. HR-MS (ESI): m/z [M þ Na]þ calcd for
acetone-d6):
d
145.0, 144.5, 134.9, 129.5, 128.7, 127.9, 122.0, 118.3,
C
30H29NNaO3: 474.2040; found: 474.2025.
116.7, 116.3, 87.5, 71.0, 66.8, 66.6, 53.3. HR-MS (ESI): m/z [M þ Na]þ
(R)-1-((S)-6-Methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-
calcd for C29H27NNaO3: 460.1883; found: 460.1862.
yl)-2-(trityloxy)ethan-1-ol (2g). Off-white solid (173 mg, 92%);
(R)-1-((R)-3,4-Dihydro-2H-benzo[b][1,4]oxazin-3-yl)-2-(trity-
loxy)ethan-1-ol (2c).White solid (149 mg, 85%); mp: 55ꢀ57 ꢁC. The
mp: 200ꢀ202 ꢁC. The product was analyzed by chiral HPLC (IC,
5
m
m, 4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 90/10; flow
product was analyzed by chiral HPLC (OZ-H,
5
m
m,
rate: 1.0 mL/min;
The enantiomeric purity of 2g was determined to be >99% ee.
l
¼ 220 nm; T ¼ 15 ꢁC): tR ¼ 16.77 min (100.0%).
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 90/10; flow rate:
21
1.0 mL/min;
l
¼ 220 nm; T ¼ 11 ꢁC): tR ¼ 9.36 min (98.46%),
[
a
]
¼ þ6.2 (c 1, EtOAc). 1H NMR (500 MHz, acetone-d6):
D
12.21 min (1.54%). The enantiomeric purity of 2c was determined to
d 7.54e7.49 (m, 6 H), 7.36e7.33 (m, 6 H), 7.29e7.26 (m, 3 H), 6.52 (d,
22
be 97% ee. [
a]
¼ ꢀ6.2 (c 1, EtOAc). 1H NMR (500 MHz, acetone-d6):
J ¼ 8.5 Hz,1 H), 6.25 (d, J ¼ 2.5 Hz,1 H), 6.08 (dd, J ¼ 3.0, 8.5 Hz,1 H),
5.07 (brs, 1 H), 4.40 (d, J ¼ 4.8 Hz, 1 H), 4.03 (dd, J ¼ 2.4, 8.8 Hz, 1 H),
3.83e3.74 (m, 2 H), 3.64 (s, 3 H), 3.54e3.51 (m, 1 H), 3.35 (dd,
J ¼ 3.6, 8.0 Hz,1 H), 3.18 (dd, J ¼ 3.6, 8.0 Hz,1 H). 13C NMR (125 MHz,
D
d
7.55e7.50 (m, 6 H), 7.36e7.33 (m, 6 H), 7.29e7.26 (m, 3 H),
6.65e6.59 (m, 2 H), 6.50e6.46 (m,1 H), 6.39 (dd, J ¼ 1.5, 8.0 Hz,1 H),
4.52 (brs, 1 H), 4.38 (d, J ¼ 5.5 Hz,1 H), 4.24 (dd, J ¼ 5.0,10.5 Hz,1 H),
4.09 (dd, J ¼ 2.5, 10.5 Hz, 1 H), 3.83e3.76 (m, 1 H), 3.55e3.51 (m,
acetone-d6):
d 155.5, 145.0, 138.5, 135.4, 129.5, 128.6, 127.9, 116.8,
1 H), 3.47 (dd, J ¼ 3.5, 9.5 Hz, 1 H), 3.22 (dd, J ¼ 5.0, 10.0 Hz, 1 H). 13
C
103.2, 101.7, 87.4, 71.1, 66.63, 66.59, 55.5, 53.4. HR-MS (ESI): m/z
[M þ Na]þ calcd for C30H29NNaO4: 490.1989; found: 490.1974.
(R)-1-((S)-7-Methoxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-
yl)-2-(trityloxy)ethan-1-ol (2h). White solid (129 mg, 69%); mp:
NMR (125 MHz, acetone-d6):
d 145.0, 144.5, 134.5, 129.5, 128.7,
127.9, 122.0, 118.1, 116.8, 115.7, 87.4, 70.4, 66.4, 66.0, 53.1. HR-MS
(ESI): m/z [M þ Na]þ calcd for C29H27NNaO3: 460.1883; found:
460.1865.
65ꢀ67 ꢁC. The product was analyzed by chiral HPLC (IC, 5
mm,
(S)-1-((S)-3,4-Dihydro-2H-benzo[b][1,4]oxazin-3-yl)-2-(trity-
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 90/10; flow rate:
loxy)ethan-1-ol (2d).White solid (117 mg, 67%); mp: 60ꢀ62 ꢁC. The
1.0 mL/min;
l
¼ 220 nm; T ¼ 15 ꢁC): tR ¼ 13.65 min (98.06%),
product was analyzed by chiral HPLC (OZ-H,
5
m
m,
16.70 min (1.94%). The enantiomeric purity of 2h was determined
22
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 90/10; flow rate:
to be 96% ee. [
a
]
D
¼ þ8.0 (c 1, CHCl3). 1H NMR (400 MHz, acetone-
1.0 mL/min;
l
¼ 220 nm; T ¼ 11 ꢁC): tR ¼ 9.45 min (2.09%),12.17 min
d6): d 7.53e7.50 (m, 6 H), 7.37e7.31 (m, 6 H), 7.30e7.23 (m, 3 H),
(97.91%). The enantiomeric purity of 2d was determined to be 96%
6.57 (d, J ¼ 8.8 Hz, 1 H), 6.31 (dd, J ¼ 2.8, 8.8 Hz, 1 H), 6.28 (d,
J ¼ 2.4 Hz, 1 H), 4.58 (brs, 1 H), 4.34 (d, J ¼ 6.4 Hz, 1 H), 4.10 (dd,
J ¼ 2.8, 10.4 Hz, 1 H), 3.86 (dd, J ¼ 7.2, 10.8 Hz, 1 H), 3.81e3.74 (m,
1 H), 3.65 (s, 3 H), 3.51e3.43 (m, 1 H), 3.35 (dd, J ¼ 4.4, 10.0 Hz, 1 H),
3.19 (dd, J ¼ 4.8, 9.6 Hz, 1 H). 13C NMR (125 MHz, acetone-d6):
21
ee. [
d
a]
¼ þ4.4 (c 1, EtOAc). 1H NMR (500 MHz, acetone-d6):
D
7.55e7.49 (m, 6 H), 7.36e7.33 (m, 6 H), 7.30e7.25 (m, 3 H),
6.63e6.60 (m, 2 H), 6.50e6.45 (m, 1 H), 6.39 (d, J ¼ 10.0 Hz, 1 H),
4.52 (brs,1 H), 4.37 (d, J ¼ 5.5 Hz,1 H), 4.23 (dd, J ¼ 5.0,10.5 Hz,1 H),
4.09 (dd, J ¼ 2.5, 10.5 Hz, 1 H), 3.81e3.77 (m, 1 H), 3.54e3.50 (m,
d
153.7, 145.4, 145.0, 129.5, 128.6, 128.2, 127.9, 117.3, 107.6, 103.1,
1 H), 3.47 (dd, J ¼ 4.0,10.0 Hz,1 H), 3.22 (dd, J ¼ 5.0,10.0 Hz,1 H). 13
C
87.5, 70.8, 67.3, 66.5, 55.7, 53.3. HR-MS (ESI): m/z [M þ Na]þ calcd
NMR (125 MHz, acetone-d6):
d 145.0, 144.5, 134.5, 129.5, 128.7,
for C30H29NNaO4: 490.1989; found: 490.1975.
127.9, 122.0, 118.1, 116.8, 115.7, 87.4, 70.4, 66.4, 66.0, 53.1. HR-MS
(ESI): m/z [M þ Na]þ calcd for C29H27NNaO3: 460.1883; found:
460.1862.
(R)-1-((S)-5-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-
yl)-2-(trityloxy)ethan-1-ol (2i). White solid (107 mg, 52%); mp:
113ꢀ114 ꢁC. The product was analyzed by chiral HPLC (OZ-H, 5
mm,
(R)-1-((S)-6-Methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-
yl)-2-(trityloxy)ethan-1-ol (2e). Off-white solid (127 mg, 71%);
mp: 152ꢀ154 ꢁC. The product was analyzed by chiral HPLC (IC,
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 97/3; flow rate:
0.6 mL/min;
l
¼ 220 nm; T ¼ 11 ꢁC): tR ¼ 26.62 min (98.39%),
31.39 min (1.61%). The enantiomeric purity of 2i was determined to
21
5
m
m, 4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 95/5; flow
be 97% ee. [
a
]
¼ ꢀ6.5 (c 1, CHCl3). 1H NMR (400 MHz, acetone-d6):
D
rate: 0.7 mL/min;
16.67 min (2.71%). The enantiomeric purity of 2e was determined to
be 95% ee. [a]
d
l
¼ 220 nm; T ¼ 17 ꢁC): tR ¼ 14.32 min (97.29%),
d 7.55e7.50 (m, 6 H), 7.38e7.31 (m, 6 H), 7.30e7.24 (m, 3 H), 6.98
(dd, J ¼ 1.2, 8.0 Hz, 1 H), 6.67 (dd, J ¼ 1.2, 8.0 Hz, 1 H), 6.50e6.46 (m,
1 H), 5.02 (brs, 1 H), 4.62 (d, J ¼ 6.0 Hz, 1 H), 4.15e4.11 (m, 1 H),
3.90e3.80 (m, 2 H), 3.67e3.62 (m, 1 H), 3.37 (dd, J ¼ 4.4, 10.0 Hz,
1 H), 3.21 (dd, J ¼ 4.4, 10.0 Hz, 1 H). 13C NMR (100 MHz, acetone-d6):
¼ þ3.2 (c 1, CHCl3). 1H NMR (500 MHz, acetone-d6):
22
D
7.56e7.50 (m, 6 H), 7.36e7.33 (m, 6 H), 7.29e7.24 (m, 3 H), 6.50 (d,
J ¼ 8.0 Hz, 1 H), 6.44 (d, J ¼ 1.5 Hz, 1 H), 6.31 (dd, J ¼ 1.5, 8.5 Hz, 1 H),
4.89 (brs, 1 H), 4.39 (d, J ¼ 6.0 Hz,1 H), 4.05 (dd, J ¼ 2.5,10.5 Hz,1 H),
3.83 (dd, J ¼ 7.0, 10.5 Hz, 1 H), 3.80e3.75 (m, 1 H), 3.55e3.49 (m,
1 H), 3.35 (dd, J ¼ 4.5, 10.0 Hz, 1 H), 3.18 (dd, J ¼ 4.5, 10.0 Hz, 1 H),
d
145.2, 144.9, 132.8, 129.5, 128.7, 127.9, 125.3, 118.6, 116.1, 109.3,
87.6, 70.9, 66.7, 66.4, 53.3. HR-MS (ESI): m/z [M þ Na]þ calcd for
C
29H26BrNNaO3: 538.0988; found: 538.0965.
10

H. Zhao, S. Li, S. Cheng et al.
Tetrahedron 93 (2021) 132304
(R)-1-((S)-6-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-
yl)-2-(trityloxy)ethan-1-ol (2j). White solid (190 mg, 92%); mp:
yl)-2-(trityloxy)ethan-1-ol (2n). White solid (128 mg, 70%); mp:
49ꢀ51 ꢁC. The product was analyzed by chiral HPLC (OZ-H, 5
mm,
75ꢀ77 ꢁC. The product was analyzed by chiral HPLC (OZ-H, 5
m
m,
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 95/5; flow rate:
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 95/5; flow rate:
1.0 mL/min;
l
¼ 220 nm; T ¼ 17 ꢁC): tR ¼ 10.61 min (98.04%),
1.0 mL/min;
l
¼ 220 nm; T ¼ 16 ꢁC): tR ¼ 10.20 min (98.75%),
14.81 min (1.96%). The enantiomeric purity of 2n was determined to
21
11.84 min (1.25%). The enantiomeric purity of 2j was determined to
be 96% ee. [
a
]
¼ þ6.2 (c 1, CHCl3). 1H NMR (400 MHz, acetone-d6):
D
22
be 98% ee. [
d6):
a
]
¼ þ22.2 (c 1, CHCl3). 1H NMR (400 MHz, acetone-
d 7.55e7.48 (m, 6 H), 7.36e7.32 (m, 6 H), 7.30e7.23 (m, 3 H), 6.63
D
d
7.55e7.48 (m, 6 H), 7.36e7.32 (m, 6 H), 7.30e7.23 (m, 3 H),
(dd, J ¼ 6.0, 8.4 Hz, 1 H), 6.50e6.41 (m, 2 H), 4.92 (brs, 1 H), 4.40 (d,
J ¼ 6.0 Hz, 1 H), 4.12 (dd, J ¼ 2.8, 10.8 Hz, 1 H), 3.89 (dd, J ¼ 3.2,
10.4 Hz, 1 H), 3.81e3.76 (m, 1 H), 3.52e3.49 (m, 1 H), 3.35 (dd,
J ¼ 4.8, 10.0 Hz, 1 H), 3.20 (dd, J ¼ 4.8, 10.0 Hz, 1 H). 13C NMR
6.82 (d, J ¼ 2.0 Hz, 1 H), 6.61 (dd, J ¼ 2.0, 8.4 Hz, 1 H), 6.55 (d,
J ¼ 8.4 Hz, 1 H), 5.37 (brs, 1 H), 4.46 (d, J ¼ 6.0 Hz, 1 H), 4.08 (dd,
J ¼ 2.8, 10.8 Hz, 1 H), 3.90e3.84 (m, 1 H), 3.81e3.74 (m, 1 H),
3.58e3.51 (m, 1 H), 3.34 (dd, J ¼ 4.0, 10.0 Hz, 1 H), 3.19 (dd, J ¼ 4.4,
(100 MHz, acetone-d6):
d
156.3 (d, J ¼ 232.0 Hz), 145.0, 144.9 (d,
9.6 Hz, 1 H). 13C NMR (100 MHz, acetone-d6):
d
145.0, 143.6, 136.8,
J ¼ 11.0 Hz), 131.3 (d, J ¼ 2.0 Hz), 129.5, 128.7, 127.9, 116.5 (d,
J ¼ 9.0 Hz), 107.9 (d, J ¼ 22.0 Hz), 104.0 (d, J ¼ 26.0 Hz), 87.5, 70.9,
129.5, 128.7, 127.9, 120.2, 118.3, 118.0, 113.7, 87.6, 71.1, 66.60, 66.55,
53.0. HR-MS (ESI): m/z [M þ Na]þ calcd for C29H26BrNNaO3:
538.0988; found: 538.0978.
(R)-1-((S)-7-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-
yl)-2-(trityloxy)ethan-1-ol (2k). White solid (190 mg, 92%); mp:
67.2, 66.5, 53.1. HR-MS (ESI): m/z [M
þ
Na]þ calcd for
C
29H26FNNaO3: 478.1789; found: 478.1780.
(R)-1-((S)-6-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-
2-(trityloxy)ethan-1-ol (2o). Yellow solid (176 mg, 91%); mp:
57ꢀ59 ꢁC. The product was analyzed by chiral HPLC (IC, 5
m
m,
78ꢀ80 ꢁC. The product was analyzed by chiral HPLC (OZ-H, 5
mm,
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 97/3; flow rate:
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 85/15; flow rate:
0.6 mL/min;
l
¼ 220 nm; T ¼ 15 ꢁC): tR ¼ 17.57 min (97.86%),
1.0 mL/min;
l
¼ 220 nm; T ¼ 17 ꢁC): tR ¼ 12.47 min (98.41%),
25.10 min (2.14%). The enantiomeric purity of 2k was determined to
15.61 min (1.59%). The enantiomeric purity of 2o was determined to
¼ þ19.1 (c 1, CHCl3). 1H NMR (400 MHz, acetone-
21
22
be 96% ee. [
d6):
a
]
be 97% ee. [
a]
¼ þ63.7 (c 1, CHCl3). 1H NMR (500 MHz, acetone-
D
D
d
7.53e7.48 (m, 6 H), 7.37e7.30 (m, 6 H), 7.30e7.23 (m, 3 H),
d6):
d
7.60 (d, J ¼ 2.5 Hz, 1 H), 7.54e7.49 (m, 6 H), 7.45 (dd, J ¼ 3.0,
6.82e6.76 (m, 2 H), 6.60 (d, J ¼ 8.4 Hz, 1 H), 5.22 (brs, 1 H), 4.44 (d,
J ¼ 6.4 Hz, 1 H), 4.10 (dd, J ¼ 2.8, 10.4 Hz, 1 H), 3.89 (dd, J ¼ 6.8,
10.4 Hz, 1 H), 3.82e3.75 (m, 1 H), 3.56e3.52 (m, 1 H), 3.33 (dd,
J ¼ 4.0, 10.0 Hz, 1 H), 3.20 (dd, J ¼ 4.8, 10.0 Hz, 1 H). 13C NMR
9.0 Hz, 1 H), 7.36e7.33 (m, 6 H), 7.30e7.23 (m, 3 H), 6.79 (d,
J ¼ 8.5 Hz,1 H), 5.82 (brs,1 H), 4.61 (d, J ¼ 6.5 Hz,1 H), 4.25e4.20 (m,
1 H), 4.03 (dd, J ¼ 6.5, 11.0 Hz, 1 H), 3.85e3.81 (m, 1 H), 3.66e3.60
(m, 1 H), 3.34 (dd, J ¼ 4.0, 10.0 Hz, 1 H), 3.23 (dd, J ¼ 5.0, 10.0 Hz,
(100 MHz, acetone-d6):
d
145.2, 145.0, 134.6, 129.5, 128.7, 127.9,
1 H). 13C NMR (125 MHz, acetone-d6):
d 149.6, 144.9, 143.0, 135.5,
124.7, 119.4, 117.3, 108.4, 87.6, 71.1, 66.8, 66.6, 53.1. HR-MS (ESI): m/z
[M þ Na]þ calcd for C29H26BrNNaO3: 538.0988; found: 538.0984.
(R)-1-((S)-8-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-
yl)-2-(trityloxy)ethan-1-ol (2l). Off-white solid (161 mg, 78%); mp:
129.5, 128.7, 127.9, 116.6, 113.8, 110.2, 87.5, 71.1, 67.1, 66.5, 52.6. HR-
MS (ESI): m/z [M þ Na]þ calcd for C29H26N2NaO5: 505.1734; found:
505.1709.
(R)-1-((S)-7-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)-
2-(trityloxy)ethan-1-ol (2p). Yellow solid (150 mg, 78%); mp:
60ꢀ62 ꢁC. The product was analyzed by chiral HPLC (IC, 5
mm,
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 95/5; flow rate:
90ꢀ91 ꢁC. The product was analyzed by chiral HPLC (IC, 5
mm,
1.0 mL/min;
l
¼ 220 nm; T ¼ 15 ꢁC): tR ¼ 11.04 min (97.67%),
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 85/15; flow rate:
14.01 min (2.33%). The enantiomeric purity of 2l was determined to
1.0 mL/min;
l
¼ 220 nm; T ¼ 15 ꢁC): tR ¼ 16.00 min (98.07%),
22
be 95% ee. [
a
]
¼ þ6.1 (c 1, CHCl3). 1H NMR (500 MHz, acetone-d6):
19.57 min (1.93%). The enantiomeric purity of 2p was determined to
D
20
d
7.53e7.51 (m, 6 H), 7.38e7.31 (m, 6 H), 7.30e7.24 (m, 3 H), 6.75
be 96% ee. [
d6):
a
]
¼ þ64.6 (c 1, CHCl3). 1H NMR (500 MHz, acetone-
D
(dd, J ¼ 1.5, 8.0 Hz, 1 H), 6.64 (d, J ¼ 1.5, 8.0 Hz, 1 H), 6.59 (t,
J ¼ 8.0 Hz,1 H), 5.32 (brs, 1 H), 4.49 (d, J ¼ 6.5 Hz,1 H), 4.21e4.18 (m,
1 H), 3.98 (dd, J ¼ 7.0, 11.0 Hz, 1 H), 3.84e3.77 (m, 1 H), 3.59e3.55
(m, 1 H), 3.33 (dd, J ¼ 4.5, 10.0 Hz, 1 H), 3.22 (dd, J ¼ 4.5, 10.0 Hz,
d
7.68 (dd, J ¼ 2.5, 9.0 Hz,1 H), 7.52e7.50 (m, 7 H), 7.36e7.32 (m,
6 H), 7.29e7.24 (m, 3 H), 6.76 (d, J ¼ 9.0 Hz, 1 H), 6.59 (brs, 1 H), 4.66
(d, J ¼ 6.0 Hz, 1 H), 4.14 (dd, J ¼ 3.0, 11.0 Hz, 1 H), 3.98 (dd, J ¼ 6.0,
11.0 Hz, 1 H), 3.89e3.84 (m, 1 H), 3.76e3.70 (m, 1 H), 3.32 (dd,
J ¼ 4.0, 10.0 Hz, 1 H), 3.23 (dd, J ¼ 4.5, 10.0 Hz, 1 H). 13C NMR
1 H). 13C NMR (125 MHz, acetone-d6):
d 144.9, 141.0, 136.4, 129.5,
128.7, 127.9, 122.8, 121.4, 115.1, 110.5, 87.5, 71.0, 67.2, 66.6, 53.2. HR-
MS (ESI): m/z [M þ Na]þ calcd for C29H26BrNNaO3: 538.0988;
found: 538.0967.
(R)-1-((S)-6-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-
yl)-2-(trityloxy)ethan-1-ol (2 m). White solid (160 mg, 88%); mp:
(125 MHz, acetone-d6): d 144.9, 142.32, 142.29, 137.9, 129.5, 128.7,
127.9,119.7,113.4,112.3, 87.6, 71.2, 66.5, 66.0, 53.3. HR-MS (ESI): m/z
[M þ Na]þ calcd for C29H26N2NaO5: 505.1734; found: 505.1715.
(R)-1-((S)-7,8-Difluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-
yl)-2-(trityloxy)ethan-1-ol (2q). White solid (147 mg, 78%); mp:
59ꢀ61 ꢁC. The product was analyzed by chiral HPLC (OZ-H, 5
m
m,
54ꢀ56 ꢁC. The product was analyzed by chiral HPLC (IC, 5
mm,
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 95/5; flow rate:
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 95/5; flow rate:
1.0 mL/min;
l
¼ 220 nm; T ¼ 17 ꢁC): tR ¼ 10.59 min (97.80%),
0.7 mL/min;
l
¼ 220 nm; T ¼ 15 ꢁC): tR ¼ 12.39 min (98.54%),
12.76 min (2.20%). The enantiomeric purity of 2m was determined
14.15 min (1.46%). The enantiomeric purity of 2q was determined to
22
21
to be 96% ee. [
a
]
¼ þ6.2 (c 1, CHCl3). 1H NMR (400 MHz, acetone-
be 97% ee. [
a
]
¼ þ7.1 (c 1, CHCl3). 1H NMR (500 MHz, acetone-d6):
D
D
d6):
d
7.54e7.49 (m, 6 H), 7.38e7.31 (m, 6 H), 7.30e7.24 (m, 3 H),
d
7.54e7.49 (m, 6 H), 7.34 (t, J ¼ 8.0 Hz, 6 H), 7.27 (t, J ¼ 7.5 Hz, 3 H),
6.58 (dd, J ¼ 5.6, 8.8 Hz, 1 H), 6.43 (dd, J ¼ 2.8, 10.4 Hz,1 H),
6.23e6.18 (m,1 H), 5.36 (brs, 1 H), 4.43 (d, J ¼ 6.4 Hz, 1 H), 4.07e4.04
(m, 1 H), 3.86e3.75 (m, 2 H), 3.57e3.53 (m, 1 H), 3.34 (dd, J ¼ 4.0,
9.6 Hz, 1 H), 3.20 (dd, J ¼ 4.8, 9.6 Hz, 1 H). 13C NMR (100 MHz,
6.64e6.56 (m, 1 H), 6.45e6.42 (m, 1 H), 5.20 (brs, 1 H), 4.50 (d,
J ¼ 6.0 Hz, 1 H), 4.20 (dd, J ¼ 2.0, 11.0 Hz, 1 H), 3.95(dd, J ¼ 7.0,
11.0 Hz, 1 H), 3.85e3.77 (m, 1 H), 3.57e3.53 (m, 1 H), 3.34 (dd,
J ¼ 4.0, 9.5 Hz,1 H), 3.21 (dd, J ¼ 4.5, 9.5 Hz,1 H). 13C NMR (125 MHz,
acetone-d6):
d
158.7 (d, J ¼ 233.0 Hz), 145.0, 140.4 (d, J ¼ 2.0 Hz),
acetone-d6):
d
144.9, 144.3 (dd, J ¼ 10.0, 231.2 Hz), 141.0 (dd,
136.1 (d, J ¼ 11.0 Hz), 129.5, 128.6, 127.9, 117.0 (d, J ¼ 10.0 Hz), 103.2
(d, J ¼ 24.0 Hz), 102.0 (d, J ¼ 27.0 Hz), 87.5, 71.1, 66.51, 66.49, 53.1.
HR-MS (ESI): m/z [M þ Na]þ calcd for C29H26FNNaO3: 478.1789;
found: 478.1773.
J ¼ 15.0, 240.0 Hz), 133.6 (dd, J ¼ 2.5, 10.0 Hz), 132.9, 129.5, 128.7,
127.9,109.4 (dd, J ¼ 3.8, 7.5 Hz),108.3 (d, J ¼ 17.5 Hz), 87.5, 70.9, 67.2,
66.5, 52.9. HR-MS (ESI): m/z [M þ Na]þ calcd for C29H25F2NNaO3:
496.1695; found: 496.1671.
(R)-1-((S)-7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-
(R)-1-((S)-6,8-Dichloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-
11

H. Zhao, S. Li, S. Cheng et al.
Tetrahedron 93 (2021) 132304
3-yl)-2-(trityloxy)ethan-1-ol (2r). White solid (149 mg, 73%); mp:
was added and stirred overnight. After standard workup, 2k was
obtained as a white solid (1.8 g, 87%). The product was analyzed by
154ꢀ156 ꢁC. The product was analyzed by chiral HPLC (OZ-H, 5
m
m,
4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 95/5; flow rate:
chiral HPLC (IC, 5
propanol, 97/3; flow rate: 0.6 mL/min;
m
m, 4.6 mm ꢂ 250 mm; eluent: hexane/iso-
1.0 mL/min;
l
¼ 220 nm; T ¼ 15 ꢁC): tR ¼ 8.84 min (98.29%),
l
¼ 220 nm; T ¼ 15 ꢁC):
11.93 min (1.71%). The enantiomeric purity of 2r was determined to
tR ¼ 17.60 min (99.14%), 25.15 min (0.86%). The enantiomeric purity
22
be 97% ee. [
a
]
¼ þ27.4 (c 1, CHCl3). 1H NMR (400 MHz, acetone-
of 2k was determined to be 98% ee.
D
d6):
d
7.54e7.48 (m, 6 H), 7.38e7.31 (m, 6 H), 7.30e7.24 (m, 3 H),
(3R,3aS)-7-Bromo-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
6.66 (d, J ¼ 2.4 Hz, 1 H), 6.59 (d, J ¼ 2.4 Hz, 1 H), 5.70 (brs, 1 H), 4.53
(d, J ¼ 6.0 Hz, 1 H), 4.19 (dd, J ¼ 3.2, 10.8 Hz, 1 H), 3.99 (dd, J ¼ 6.4,
10.8 Hz, 1 H), 3.84e3.78 (m, 1 H), 3.62e3.57 (m, 1 H), 3.32 (dd,
J ¼ 4.4, 10.0 Hz, 1 H), 3.22 (dd, J ¼ 4.8, 10.0 Hz, 1 H). 13C NMR
benzo[b]oxazolo[3,4-d][1,4]oxazine (4). To a solution of 2k
(200 mg, 0.39 mmol) in toluene (5 mL) in a sealed tube was added
paraformaldehyde (120 mg). The sealed tube was heated for 2 h at
120 ꢁC. After cooling to room temperature, the mixture was purified
(100 MHz, acetone-d6):
d
144.9, 138.8, 137.4, 129.5, 128.7, 127.9,
by column chromatography eluting with 10e15% EtOAc in PE to
21
126.1, 121.9, 117.1, 113.5, 87.6, 71.1, 66.9, 66.5, 53.0. HR-MS (ESI): m/z
give 4 (106 mg, 52%) as a white solid. mp: 108ꢀ110 ꢁC. [
a
]
¼ þ6.36
D
[M þ Na]þ calcd for C29H25Cl2NNaO3: 528.1104; found: 528.1094.
(c 1, CHCl3). 1H NMR (400 MHz, CDCl3):
d 7.47e7.41 (m, 6 H),
tert-Butyl
(S)-3-((R)-1-hydroxy-2-(trityloxy)ethyl)-3,4-
7.35e7.28 (m, 6 H), 7.27e7.22 (m, 3 H), 7.02 (d, J ¼ 2.4 Hz, 1 H), 6.99
(dd, J ¼ 2.0, 8.4 Hz, 1 H), 6.48 (d, J ¼ 8.4 Hz, 1 H), 4.99 (d, J ¼ 3.6 Hz,
1 H), 4.80 (d, J ¼ 3.6 Hz, 1 H), 4.39 (dd, J ¼ 3.2, 10.8 Hz, 1 H),
3.93e3.87 (m, 1 H), 3.65 (dd, J ¼ 7.2, 10.8 Hz, 1 H), 3.56e3.51 (m,
dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (2s). White solid
(161 mg, 75%); mp: 78ꢀ80 ꢁC. The product was analyzed by chiral
HPLC (IC, 5
10; flow rate: 0.8 mL/min;
(1.60%), 21.84 min (98.40%). The enantiomeric purity of 2s was
determined to be 97% ee. [
m
m, 4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 90/
l
¼ 220 nm; T ¼ 15 ꢁC): tR ¼ 18.56 min
1 H), 3.48 (dd, J ¼ 4.8, 9.6 Hz, 1 H), 3.31 (dd, J ¼ 6.0, 10.0 Hz, 1 H). 13
C
NMR (125 MHz, CDCl3): d 145.2, 143.5, 132.3, 128.6, 128.0, 127.2,
21
a
]
¼ þ24.8 (c 1, CHCl3). 1H NMR
125.1, 119.8, 117.2, 111.3, 87.1, 84.1, 77.5, 64.7, 64.0, 57.5. HR-MS (ESI):
m/z [M þ Na]þ calcd for C30H26BrNNaO3: 550.0988; found:
550.0969.
(4R,4aS)-8-Bromo-4-((trityloxy)methyl)-1,2,4a,5-tetrahydro-
4H-benzo[b][1,4]oxazino[4,3-d][1,4]oxazine (5). The title com-
pound 5 was prepared referring to the literature method [16]. A
solution of 2k (515 mg, 1 mmol) in anhydrous DCM (30 mL) was
treated with NaH (60%, 200 mg, 5 mmol) at 0 ꢁC under argon. After
D
(500 MHz, acetone-d6):
d
7.54e7.49 (m, 6 H), 7.37e7.31 (m, 7 H),
7.29e7.21 (m, 4 H), 6.65 (d, J ¼ 8.0 Hz, 1 H), 5.79 (brs, 1 H), 4.53 (d,
J ¼ 6.0 Hz, 1 H), 4.09 (dd, J ¼ 3.0, 10.5 Hz, 1 H), 3.90 (dd, J ¼ 6.5,
11.0 Hz, 1 H), 3.85e3.79 (m, 1 H), 3.67e3.59 (m, 1 H), 3.33 (dd,
J ¼ 4.0, 10.0 Hz, 1 H), 3.21 (dd, J ¼ 4.5, 10.0 Hz, 1 H), 1.53 (s, 9 H). 13
C
NMR (125 MHz, acetone-d6):
d 166.1, 144.9, 142.9, 139.5, 129.5,
128.7,127.9,124.4,121.0,117.8,114.3, 87.5, 79.8, 71.2, 66.6, 66.3, 53.3,
28.4. HR-MS (ESI): m/z [M þ Na]þ calcd for C34H35NNaO5: 560.2407;
found: 560.2389.
5
min,
(2-bromoethyl)diphenylsulfonium
tri-
fluoromethanesulfonate (1.1 g, 2.5 mmol) was added and the
mixture was stirred for 3 h at 0 ꢁC, followed by 12 h at room
temperature. The reaction was then quenched with water (10 mL),
extracted with DCM, washed with brine, dried over Na2SO4, filtered
and concentrated in vacuum. After chromatography eluting with
(R)-1-((S)-7-(Piperidin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]
oxazin-3-yl)-2-(trityloxy)ethan-1-ol (2t). Pale yellow solid
(162 mg, 78%); mp: 73ꢀ75 ꢁC. The product was analyzed by chiral
HPLC (IC, 5
15; flow rate: 1.0 mL/min;
(98.78%), 13.30 min (1.22%). The enantiomeric purity of 2t was
determined to be 98% ee. [
(400 MHz, acetone-d6):
m
m, 4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 85/
l
¼ 220 nm; T ¼ 16 ꢁC): tR ¼ 9.52 min
5e10% EtOAc in PE, compound 5 was obtained as an off-white solid
20
(284 mg, 52%). mp: 205ꢀ206 ꢁC. [
a
]
¼ þ8.28 (c 1, CHCl3). 1H NMR
D
22
a
]
¼ þ12.8 (c 1, CHCl3). 1H NMR
(400 MHz, DMSO-d6):
d
7.44e7.32 (m, 12 H), 7.28 (t, J ¼ 6.8 Hz, 3 H),
D
d
7.54e7.48 (m, 6 H), 7.37e7.32 (m, 6 H),
6.95 (dd, J ¼ 2.4, 8.8 Hz, 1 H), 6.87e6.81 (m, 2 H), 4.06 (dd, J ¼ 3.2,
11.2 Hz, 1 H), 3.91 (dd, J ¼ 2.8, 10.8 Hz, 1 H), 3.83 (dd, J ¼ 8.4, 10.4 Hz,
1 H), 3.68e3.59 (m, 2 H), 3.36e3.26 (m, 2 H), 3.23e3.16 (m, 1 H),
2.94 (dd, J ¼ 3.2, 10.8 Hz, 1 H), 2.81e2.71 (m, 1 H). 13C NMR
7.29e7.24 (m, 3 H), 6.53 (d, J ¼ 8.4 Hz, 1 H), 6.37 (d, J ¼ 7.6 Hz, 1 H),
6.31 (s, 1 H), 4.52 (brs, 1 H), 4.30 (d, J ¼ 6.4 Hz, 1 H), 4.08 (dd, J ¼ 2.8,
10.4 Hz, 1 H), 3.85 (dd, J ¼ 7.2, 10.8 Hz, 1 H), 3.80e3.73 (m, 1 H), 3.47
(brs, 1 H), 3.35 (dd, J ¼ 4.4, 10.0 Hz, 1 H), 3.18 (dd, J ¼ 4.8, 10.0 Hz,
1 H), 2.92 (t, J ¼ 5.6 Hz, 4 H), 1.66e1.61 (m, 4 H), 1.52e1.47 (m, 2 H).
(100 MHz, DMSO-d6): d 145.0, 143.4, 134.6, 128.1, 128.0, 127.2, 123.7,
118.1, 114.9, 109.5, 86.0, 74.9, 65.6, 65.0, 63.4, 52.9, 45.0. HR-MS
(ESI): m/z [M þ H]þ calcd for C31H27BrNO4: 542.1325; found:
542.1302.
13C NMR (125 MHz, acetone-d6):
d 146.7, 145.1, 145.0, 129.5, 128.6,
127.9, 117.2, 111.9, 106.7, 87.4, 70.8, 67.2, 66.5, 53.4, 52.8, 26.9, 25.0.
HR-MS (ESI): m/z [MþH]þ calcd for C34H37N2O3: 521.2799; found:
521.2787.
Gram-scale synthesis of (R)-1-((S)-7-Bromo-3,4-dihydro-2H-
benzo[b][1,4]oxazin-3-yl)-2-(trityloxy)ethan-1-ol (2k). A mixture
of 1m (4.1 g, 6.8 mmol) and KOH (0.96 g, 17 mmol) in anhydrous
THF (40 mL) was stirred at room temperature under argon for 8 h.
After solution workup and purification by chromatography
(15e20% EtOAc in PE), the title compound 2k was obtained as a
white solid (3.4 g, 97%). The product was analyzed by chiral HPLC
(4R,4aS)-8-Bromo-4-((trityloxy)methyl)-4a,5-dihydro-4H-
benzo[b][1,4]oxazino[4,3-d][1,4]oxazin-1(2H)-one (6). Compound
6 was prepared referring to the literature method [17]. A solution of
2k (515 mg, 1 mmol) in anhydrous THF (8 mL) under argon was
treated with t-BuOK (168 mg, 1.5 mmol) at room temperature. After
5 min, ethyl chloroacetate (0.16 mL, 1.5 mmol) was added, and the
reaction mixture was stirred for 7 h. Brine was added, the mixture
was extracted with EtOAc. The combined organic layer was washed
with brine, dried over Na2SO4, filtered and concentrated in vacuum.
The residue was purified by chromatography (18% EtOAc in PE) to
(IC, 5
m
m, 4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 97/3;
flow rate: 0.6 mL/min;
(99.15%), 25.04 min (0.85%). The enantiomeric purity of 2k was
determined to be 98% ee.
l
¼ 220 nm; T ¼ 15 ꢁC): tR ¼ 17.53 min
give the title compound 6 as a white solid (330 mg, 59%). mp:
19
161ꢀ162 ꢁC. [
a
]
¼ þ45.4 (c 1, CHCl3). 1H NMR (400 MHz, acetone-
D
d6):
d
8.22 (d, J ¼ 8.8 Hz,1 H), 7.54e7.49 (m, 6 H), 7.40e7.33 (m, 6 H),
One-pot synthesis of (R)-1-((S)-7-Bromo-3,4-dihydro-2H-
benzo[b][1,4]oxazin-3-yl)-2-(trityloxy)ethan-1-ol (2k). To an ice
cooled mixture of propyl (4-bromo-2-hydroxyphenyl)carbamate
(1.1 g, 4 mmol), ((2R,3S)-3-((trityloxy)methyl)oxiran-2-yl)methanol
(1.9 g, 5.4 mmol) and PPh3 (1.6 g, 6 mmol) was added DIAD (1.2 mL,
6 mmol) under argon. The reaction mixture was allowed to warm to
room temperature and stirred for 5 h, then KOH (1.1 g, 20 mmol)
7.32e7.26 (m, 3 H), 7.08e7.02 (m, 2 H), 4.44 (d, J ¼ 16.4 Hz, 1 H),
4.25e4.11 (m, 3 H), 4.04e3.96 (m, 1 H), 3.86e3.82 (m, 1 H), 3.56 (dd,
J ¼ 3.2, 10.8 Hz, 1 H), 3.37 (dd, J ¼ 4.4, 10.8 Hz, 1 H). 13C NMR
(125 MHz, acetone-d6):
d 165.1, 147.7, 144.6, 129.4, 128.8, 128.1,
125.6, 124.7, 124.0, 120.4, 117.6, 87.8, 74.3, 69.0, 67.3, 64.5, 54.4. HR-
MS (ESI): m/z [M þ H]þ calcd for C31H27BrNO4: 556.1118; found:
556.1101.
12

H. Zhao, S. Li, S. Cheng et al.
Tetrahedron 93 (2021) 132304
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The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
A. Mitchell, B.S. Rao, R.P. Slatcher, L.H. Smith, M.A. Stevens,
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This work was financially supported by the National Natural
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132304.
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