Efficient and stereoselective one-pot synthesis of benzo[b] oxazolo[3,4- d] [1,4]oxazin-1-ones

Article abstract of DOI:10.1039/d0ra04104a

An efficient and mild one-pot convergent synthesis protocol has been developed for benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one derivatives through the Mitsunobu reaction and sequential cyclization. Various tricyclic fused benzoxazinyl-oxazolidinones (20 examp

Full text of DOI:10.1039/d0ra04104a

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Efficient and stereoselective one-pot synthesis of
benzo[b]oxazolo[3,4-d][1,4]oxazin-1-ones†
Cite this: RSC Adv., 2020, 10, 24037
Hongyi Zhao, Wenting Zhao, Shihao Cheng, Haijia Lu, Dongfeng Zhang *ab
ab
ab
ab
ab
ab
and Haihong Huang*
An efficient and mild one-pot convergent synthesis protocol has been developed for benzo[b]oxazolo[3,4-
d][1,4]oxazin-1-one derivatives through the Mitsunobu reaction and sequential cyclization. Various tricyclic
fused benzoxazinyl-oxazolidinones (20 examples) were obtained in good to excellent yields and high
enantioselectivities with facile operation. Furthermore, four stereoisomers were afforded respectively in
high ee values (>97.8%) via using different chiral 2,3-epoxy-4-trityloxybutanol. This methodology has
been applied to the synthesis of key intermediates of drug candidates.
Received 7th May 2020
Accepted 5th June 2020
DOI: 10.1039/d0ra04104a
rsc.li/rsc-advances
4b,8
linear synthetic routes (6–7 steps).
Chen et al. reported the
Introduction
synthesis of FXa inhibitors exemplied by 6 from substituted
Oxazolidinone was a key scaffold for some pharmaceuticals. As benzyl(2-hydroxyphenyl)carbamate
shown in Fig. 1, Linezolid (1) was the rst approved (2000) (bromomethyl)oxirane-2-carboxylate in the presence of Cs
and
methyl
3-
CO
1
,
2
3
9
oxazolidinone antibacterial drug for the treatment of Gram- which gave a moderate cyclization yield (54%). Malhotra et al.
positive bacterial infection with the off-label use to treat provided an approach for the synthesis of chiral benzoxazinyl-
complicated MDR-TB and XDR-TB. Another oxazolidinone drug oxazolidinone from benzo[b][1,4]-oxazine-3-carboxylic acid via
Tedizolid phosphate was approved by FDA in June 2014 for the 3–5 steps of derivatization including acylation, reduction,
2
10
treatment of MRSA skin infections. Furthermore, Rivaroxaban Grignard reaction and cyclization reaction. Although these
launched in 2011 is a FXa inhibitor as an anticoagulant drug methods provided access to benzo[b]oxazolo[3,4-d][1,4]oxazin-1-
3
containing the oxazolidinone moiety. Benzo[b]oxazolo[3,4-d] one analogues, the reported routes suffered from limitations to
[1,4]oxazin-1-one,
a
[6,6,5] tricyclic fused benzoxazinyl- some extent such as ineffective stereoselectivity, limited
oxazolidinone, was developed based on the oxazolidinone substrates scope, unsatisfactory yields, harsh reaction condi-
scaffold and is the essential structural framework of several tions or tedious synthesis steps. Therefore, the development of
4
5
bioactive compounds with antibacterial, anticoagulant, and a practical and efficient approach to benzo[b]oxazolo[3,4-d][1,4]
6
antituberculosis activities (Fig. 2).
oxazin-1-one is still required.
To the best of our knowledge, four synthetic routes for the
In recent years, our group have developed a series of
6,11
synthesis of benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one derivatives benzoxazinyl-oxazolidinones as anti-TB agents.
To improve
have been reported (Scheme 1). Nicolaou's group reported the the efficiency of synthesis and avoid oxidation of the sulde in
synthesis of tricyclic fused benzoxazinyl-oxazolidinone via the thiomorpholine, a convergent protocol has been devel-
11
Dess–Martin periodinane-mediated cascade cyclization of g,d- oped, however, tedious column purication and harsh cycli-
7
unsaturated urethanes in moderate yields (36–50%). Yang's zation conditions posed a hurdle for further derivatization and
group disclosed the synthesis of tricyclic fused oxazolidinone large-scale preparation. As our continuing efforts toward the
via n-BuLi mediated intramolecular cyclization reaction in
a
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation,
Institute of Materia Medica, Peking Union Medical College, Chinese Academy of
Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China. E-mail:
zdf@imm.ac.cn; joyce@imm.ac.cn
b
Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug
Research, Institute of Materia Medica, Peking Union Medical College, Chinese
Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China
†
Electronic supplementary information (ESI) available: Synthetic procedures for
1
13
the substrates and their spectroscopic characterization, H and C NMR spectra
for compounds, chiral HPLC chromatograms of compounds 9 and 11. See DOI:
Fig. 1 Chemical structure of oxazolidinone drugs.
1
0.1039/d0ra04104a
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model substrates to optimize the Mitsunobu reaction condi-
tions (Table 1). When R is Boc of 8a, the reaction furnished 10a
in good yield (81%) in the presence of DEAD and PPh3 in
anhydrous THF (entry 1). Employment of DIAD resulted in
a similar yield (entry 2).
However, this reaction did not work when TMAD or ADDP
was used (entries 3 and 4). When R is Cbz of 8b, only a trace
product was observed in the presence of ADDP (entry 5). DEAD
and DIAD could promote the reaction of 8b and 9a efficiently to
Fig. 2 Bioactive compounds containing benzo[b]oxazolo[3,4-d][1,4] afford the desired product 10b in 94% and 90% yields (entries 6
oxazin-1-one scaffold.
and 7), respectively, which was superior to the corresponding N-
Boc substrate 8a. Another polar aprotic solvent, MeCN, was also
tested and the yields for 10b using DEAD or DIAD as azo agent
development of novel benzoxazinyl-oxazolidinones as anti-TB
agents, herein, we report the rst efficient protocol for one- were found to be similar with THF (entries 8 and 9). Based on
pot and convergent synthesis of tricyclic fused benzoxazinyl- the above results and the safety consideration of dialkyl azodi-
12
oxazolidinone compounds by the reaction of benzyl(2- carboxylates, the combination of DIAD and PPh
3
was selected
hydroxyphenyl)carbamate with 2,3-epoxy-4-trityloxybutanol to be the optimized conditions and N-Cbz-2-aminophenol was
a privilege substrate.
through the Mitsunobu reaction and sequential cyclization in
mild conditions (Scheme 1).
Next, we examined the optimization of the cyclization reac-
tion conditions (Table 2). 11aa was obtained in 69% yield, when
ꢁ
1
0b was treated with n-BuLi (1.3 equiv.) from ꢀ78 C to room
Results and discussion
temperature (entry 1). Consideration of danger of n-BuLi and
harsh reaction condition, this reaction was not suitable for
scale-up preparation. We noted that the lithium ion plays a very
important role in region-chemical control and cyclization in the
As the key substrate in the Mitsunobu reaction, ((2R,3S)-3-
((trityloxy)methyl)oxiran-2-yl)methanol 9a could be synthesized
easily from (Z)-4-(trityloxy)but-2-en-1-ol by Sharpless epoxida-
13
synthesis of Linezolid. It prompted us to replace dangerous n-
BuLi by other lithium salts such as LiOH$H O, Li CO and t-
BuOLi. As depicted in Table 2, LiOH$H O and Li CO failed to
tion in excellent yield with high ee value according to the re-
5a
2
2
3
ported procedure, and the trityl protection group could be
removed smoothly under acid condition as well. Thus, at the
outset of our attempt, N-Boc or N-Cbz substituted 2-amino-
phenol derivatives 8a and 8b, compound 9a were chosen as
2
2
3
produce the expected product (entries 2 and 3). To our delight, t-
BuOLi was found very effective for this reaction (entry 4),
generating 11aa in an excellent yield (86%) at room tempera-
ture. However, the annulation process did not occur in the
2 3 2 3
presence of Cs CO and K CO (entries 5 and 6). Although t-
BuOLi could also promote the cyclization in the solvent of
MeCN with the desired product 11aa obtained in 85% yield aer
12 h at room temperature, it was difficult to stir the reaction
a
Table 1 Optimization of Mitsunobu reaction conditions
b
Entry
R
Azo agents
Phosphine
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
Boc
Boc
Boc
Boc
Cbz
Cbz
Cbz
Cbz
Cbz
DEAD
DIAD
TMAD
ADDP
ADDP
DEAD
DIAD
DEAD
DIAD
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
PPh
3
3
3
3
3
3
3
3
3
THF
THF
THF
THF
THF
THF
THF
MeCN
MeCN
81
80
Trace
Trace
Trace
94
90
82
91
a
Reaction conditions: 8a or 8b (1 mmol), 9a (1.35 mmol), azo agent (1.5
ꢁ
b
Scheme 1 Synthetic approaches to benzo[b]oxazolo[3,4-d][1,4]oxa- mmol), PPh (1.5 mmol), solvent (8 mL), 0 C–rt, 4 h. Isolated yields.
3
zin-1-ones.
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a
Table 2 Optimization of cyclization reaction conditions
consumption of the base. The result demonstrated that the
desired product 11aa can be synthesized by simple one-pot
operation with higher isolated yield (83%) compared to the
stepwise process (77%).
Encouraged by the success of one-pot protocol, subse-
quently, the generality of this one-pot process leading to the
benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one skeleton using various
combinations of substrates was investigated. As summarized in
b
Entry
Base
Solvent
Temp.
Yield (%)
ꢁ
1
2
3
4
5
6
n-BuLi
LiOH$H
THF
THF
THF
THF
THF
THF
MeCN
ꢀ78 C–rt
69
—
—
86
—
—
85
2
O
rt
rt
rt
rt
rt
rt
Table 4 Scope of one-pot synthesis of benzo[b]oxazolo[3,4-d][1,4]
Li
t-BuOLi
Cs CO
CO
t-BuOLi
2
CO
3
b
oxazin-1-ones
2
3
K
2
3
c
7
a
Reaction conditions: 10b (1 mmol), base (1.3 mmol), solvent (8 mL), rt,
h. Isolated yields. Reaction time was 12 h.
b
c
6
mixture due to the solid precipitation formed (entry 7). The
results displayed that t-BuOLi was an excellent base for the
annulation process given the stability and mild condition
compared with n-BuLi. Thus, 1.3 equiv. of t-BuOLi in THF at
room temperature was identied as the optimal cyclization
condition.
Considering the tedious column chromatography purica-
tion aer the Mitsunobu reaction, we wonder if one-pot strategy
could be applied to simplify the process. Since the reaction
solvent (THF) was not only suitable for the Mitsunobu reaction
(step 1), but also for the cyclization reaction (step 2), we
explored the possibility of cyclization reaction by adding t-
BuOLi directly into the mixture when the Mitsunobu reaction
was completed without any puried treatment (Table 3). When
1.3 or 1.5 equiv. of t-BuOLi was used, no product was detected
(entries 1 and 2). We were pleased to nd that the target
compound 11aa was obtained in 60% yield using 2.0 equiv. of t-
BuOLi. The yield of 11aa was further improved (83%) when 2.5
equiv. of t-BuOLi was employed. It indicated that diisopropyl
hydrazine-1,2-dicarboxylate, the byproduct of the Mitsunobu
+
reaction, may form the complex with Li to cause the
a
Table 3 Optimization of one-pot reaction conditions
b
Entry
Equiv. of t-BuOLi
Yield (%)
1
2
3
4
1.3
1.5
2.0
2.5
—
—
60
83
a
Reaction conditions: 8b–8r (1 mmol), 9a–9d (1.35 mmol), DIAD (1.5
ꢁ
mmol), PPh
3
(1.5 mmol), THF (8 mL), 0 C–rt, 8 h for 11ab and 11ac,
a
Reaction conditions: 8b (1 mmol), 9a (1.35 mmol), DIAD (1.5 mmol), 6 h for 11ad and 11ae, 4 h for the others; then t-BuOLi (2.5 mmol),
ꢁ
b
c
PPh (1.5 mmol), THF (8 mL), 0 C–rt, 4 h; then t-BuOLi, THF, rt, 6 h. THF, rt, 1–3 h. Isolated yields via column chromatography. Isolated
3
b
Isolated yields.
yields via trituration with MeOH and ltration.
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Table 4, rst, the reaction of benzyl(2-hydroxyphenyl)carbamate
8b with different chiral 2,3-epoxy-4-trityloxybutanol was
explored. Delightfully, four isomers were afforded smoothly in
good to excellent yields and high ee values ((3R,3aS)-11aa: 83%
yield, 98.9% ee; (3S,3aR)-11b: 67% yield, 97.8% ee; (3R,3aR)-11c: Scheme 3 Application of the methodology.
73% yield, >99% ee; (3S,3aS)-11d: 80% yield, >99% ee).
Benzyl(2-hydroxyphenyl)carbamate substituted
with
electron-donating groups such as methyl and methoxy delivered
the corresponding target compounds 11ab–11ae in 77–85%
yields with excellent enantioselectivities (96.2 to >99% ee).
Halogenated benzyl(2-hydroxyphenyl)carbamates furnished the
halogenated target compounds 11af–11an in 79–88% yields
with high enantiomeric purity (95.1 to >99% ee). As anticipated,
the electron-decient benzyl(2-hydroxyphenyl)carbamates
bearing nitro group performed efficiently to deliver the corre-
sponding target compounds 11ao and 11ap in 80% yield, >99%
ee and 74% yield, >99% ee respectively. In addition, the reaction
was also efficient when benzyl(2-hydroxyphenyl)carbamate
bearing morpholin-3-one group, leading to the desired
product 11aq in 62% yield and >99% ee, a key intermediate for
the synthesis of anticoagulant agent 6 shown in Fig. 1. It was
worth noting that the reaction time of the Mitsunobu reaction
was different depending on different substrate. When the
Conclusion
In summary, we have developed a practical, efficient and opera-
tionally simple one-pot convergent protocol to afford the tricyclic
fused benzoxazinyl-oxazolidinones through the Mitsunobu reac-
tion and sequential cyclization. The present methodology is
a stereoselective process which was controlled by the chiral 2,3-
epoxy-4-trityloxybutanol, delivering a series of benzo[b]oxazolo
[3,4-d][1,4]oxazin-1-ones in good to excellent yields (62–88%) with
high ee values (95.1 to >99% ee). In addition, this one-pot strategy
was suitable for large-scale preparation, which has been
successfully employed to afford the important intermediates of
some promising candidate compounds such as 5 and 6.
Experimental
substrate 8 containing electron-withdrawing substituent on the General
phenyl ring or non-substituted, 4 hours was sufficient for the
Mitsunobu reaction (11aa, 11b–11d and 11af–11ap), while
benzyl(2-hydroxyphenyl)carbamate containing electron-
donating groups, the reaction took 6–8 hours (11ab–11ae). It
is apparently that the electron-withdrawing group is benecial
to speed up the reaction due to increasing the acidity of the
Unless otherwise stated, all the solvents and reagents were
purchased from commercial suppliers and were used without
further purication. All melting points were measured with
a micro melting point apparatus (MP-J3, Yanaco) and were
1
13
uncorrected. H NMR or C NMR spectra were recorded on
Varian 400 MHz or 500 MHz spectrometer using CDCl , DMSO-
or acetone-d as solvents and tetramethylsilane (TMS) as an
3
2
phenol hydroxyl, exemplied by 4 h for 11ap (R is 4-NO ) vs. 8 h
d
6
6
for 11ac (R is 4-MeO). Taking the advantage of some rigid
tricyclic fused oxazolidinones with low solubility in MeOH, we
simplied the purication only via trituration with MeOH and
then by ltration to afford the pure products. Notably, the
excellent enantioselectivity (>99% ee) was observed aer the
simple operation, represented by 11c, 11d, 11ac, 11af, and
internal standard. HR-MS spectra were obtained on a Thermo-
Fisher Exactive Plus mass spectrometer (ESI, ThermoFisher
Scientic, Bremen, Germany). Optical rotations were measured
with a Rudolph Research Analytical (Autopol IV-T).
General procedure for the synthesis of target compounds
11an–11aq.
To further explore the scalability and potential synthetic To a mixture of 8 (1.0 equiv.), 9 (1.35 equiv.), PPh (1.5 equiv.) in
3
ꢁ
application of the present method, the gram-scale reaction and anhydrous THF (8 mL) at 0 C was added dropwise a solution of
application were carried out. As displayed in Schemes 2 and 3, DIAD (1.5 equiv.) in anhydrous THF (0.3 mL). The reaction
ꢁ
1
1ah was obtained in good yield (1.7 g, 74%, >99% ee) aer mixture was stirred at 0 C for 30 min. Then, the reaction was
triturating in MeOH. Next, the deprotection of the triphe- allowed to warm to room temperature and monitored by TLC.
nylmethyl group of 11ah was performed well under mild Upon the completion of reaction, t-BuOLi (2.5 equiv.) was
condition. Aer aqueous workup and trituration with DCM/PE added, and the reaction mixture was stirred at room tempera-
(1/1), compound 12 was obtained in 89% yield, and then the ture for 1–3 h. Aer the reaction completed, water (20 mL) was
Suzuki–Miyaura reaction of 12 and bis(pinacolato)diboron added to quench the reaction, the reaction mixture was
provided the corresponding borate ester 13 (80%) which was an extracted with EtOAc (15 mL ꢂ 3). The combined organic phase
2 4
important intermediate to synthesize the clinical candidate 5 was washed with brine (15 mL), dried over anhydrous Na SO ,
4c,14
(Fig. 1) as an antibacterial agent.
and evaporated in vacuum. The residue was puried by column
chromatography or triturating with MeOH to give the products
11.
(
3R,3aS)-3-((Trityloxy)methyl)-3a,4-dihydro-1H,3H-benzo
[
(
b]oxazolo[3,4-d][1,4]oxazin-1-one (11aa). White solid
385 mg, 83% yield); mp: 175–177 C. The product was
ꢁ
analyzed by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm;
ꢀ1
Scheme 2 Gram-scale synthesis of compound 11ah.
eluent: hexane/isopropanol, 80/20; ow rate: 1 mL min ; l
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220 nm; T ¼ 20 C): t
RSC Advances
ꢁ
¼
R
¼ 12.06 min (99.46%), t
R
¼
MHz, acetone-d
6
) d: 154.4, 145.2, 144.4, 129.4, 128.9, 128.2,
4.30 min (0.54%). The enantiomeric purity of 11aa was 125.6, 124.5, 122.5, 118.5, 117.9, 88.1, 74.6, 64.3, 63.0, 54.2.
1
2
1
1
+
determined to be 98.9% ee. [a]D ¼ ꢀ33.9 (c ¼ 1, CHCl ). H HR-MS (ESI): m/z [M + Na] calcd for C H NNaO : 486.1676;
3
30 25
4
NMR (400 MHz, acetone-d ) d: 7.98–7.94 (m, 1H), 7.53–7.48 found: 486.1672.
6
(
m, 6H), 7.39–7.32 (m, 6H), 7.31–7.26 (m, 3H), 7.07–6.96 (m,
(3R,3aS)-8-Methoxy-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
2
1
H), 6.95–6.90 (m, 1H), 4.66–4.59 (m, 1H), 4.54 (dd, J ¼ 2.8, benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11ab). White solid
ꢁ
0.4 Hz, 1H), 4.14–4.08 (m, 1H), 4.02 (t, J ¼ 10.0 Hz, 1H), 3.61 (379 mg, 77% yield); mp: 145–147 C. The product was analyzed
1
3
(
dd, J ¼ 4.0, 10.4 Hz, 1H), 3.46 (dd, J ¼ 4.4, 10.4 Hz, 1H).
C
by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: hexane/
ꢀ1
NMR (100 MHz, acetone-d
6
) d: 154.7, 145.7, 144.7, 129.5, isopropanol, 70/30; ow rate: 1 mL min ; l ¼ 210 nm; T ¼ 25
ꢁ
1
6
28.9, 128.2, 125.2, 124.9, 122.1, 120.4, 117.7, 87.8, 75.5,
C): tR ¼ 12.82 min (98.09%), t ¼ 15.68 min (1.91%). The
R
+
7.2, 64.9, 53.7. HR-MS (ESI): m/z [M + Na] calcd for enantiomeric purity of 11ab was determined to be 96.2% ee.
2
1
1
C30H25NNaO : 486.1676; found: 486.1670.
[a] ¼ ꢀ17.8 (c ¼ 1, CHCl ). H NMR (500 MHz, acetone-d ) d:
4
D
3
6
(
3S,3aR)-3-((Trityloxy)methyl)-3a,4-dihydro-1H,3H-benzo 7.61 (d, J ¼ 2.5 Hz, 1H), 7.56–7.46 (m, 6H), 7.42–7.32 (m, 6H),
[
(
b]oxazolo[3,4-d][1,4]oxazin-1-one (11b). White solid 7.32–7.25 (m, 3H), 6.85 (d, J ¼ 9.0 Hz, 1H), 6.62 (dd, J ¼ 2.5,
ꢁ
310 mg, 67% yield); mp: 184–186 C. The product was 9.0 Hz, 1H), 4.65–4.57 (m, 1H), 4.47 (dd, J ¼ 3.0, 10.5 Hz, 1H),
analyzed by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; 4.14–4.04 (m, 1H), 3.95 (t, J ¼ 10.5 Hz, 1H), 3.77 (s, 3H), 3.60 (dd, J
ꢀ1
13
eluent: hexane/isopropanol, 80/20; ow rate: 1 mL min ; l ¼ 3.5, 10.5 Hz, 1H), 3.46 (dd, J ¼ 4.5, 10.5 Hz, 1H). C NMR (100
ꢁ
¼
220 nm; T ¼ 20 C): t ¼ 12.05 min (1.10%), t ¼ 14.23 min MHz, acetone-d ) d: 155.1, 154.6, 144.7, 139.6, 129.5, 128.9, 128.2,
R
R
6
(
98.90%). The enantiomeric purity of 11b was determined to 125.1, 118.1, 111.0, 105.3, 87.9, 75.5, 67.0, 64.8, 56.0, 54.0. HR-MS
2
1
1
+
be 97.8% ee. [a]D ¼ +33.1 (c ¼ 1, CHCl ). H NMR (500 MHz, (ESI): m/z [M + Na] calcd for C H NNaO : 516.1781; found:
3
31 27
5
acetone-d
6
) d: 7.96 (dd, J ¼ 1.0, 7.5 Hz, 1H), 7.56–7.44 (m, 516.1762.
6
6
3
3
H), 7.40–7.32 (m, 6H), 7.32–7.24 (m, 3H), 7.08–6.96 (m, 2H),
(3R,3aS)-7-Methoxy-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
.94 (dd, J ¼ 1.5, 8.0 Hz, 1H), 4.66–4.58 (m, 1H), 4.53 (dd, J ¼ benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11ac). White solid
ꢁ
.0, 10.5 Hz, 1H), 4.16–4.06 (m, 1H), 4.02 (t, J ¼ 10.5 Hz, 1H), (403 mg, 82% yield); mp: 220–222 C. The product was analyzed
.61 (dd, J ¼ 4.0, 10.5 Hz, 1H), 3.46 (dd, J ¼ 4.0, 10.5 Hz, 1H). by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: hexane/
1
3
ꢀ1
C NMR (100 MHz, acetone-d ) d: 154.7, 145.8, 144.7, 129.5, isopropanol, 70/30; ow rate: 1 mL min ; l ¼ 210 nm; T ¼ 25
6
ꢁ
1
6
C
28.9, 128.2, 125.2, 124.9, 122.1, 120.4, 117.7, 87.8, 75.5,
C): t ¼ 13.88 min (100.00%). The enantiomeric purity of 11ac
R
+
21 1
7.2, 64.9, 53.7. HR-MS (ESI): m/z [M + Na] calcd for was determined to be >99% ee. [a] ¼ ꢀ27.1 (c ¼ 1, CHCl ). H
D
3
30
H
25NNaO
4
: 486.1676; found: 486.1663.
NMR (400 MHz, acetone-d
6
) d: 7.78 (d, J ¼ 9.2 Hz, 1H), 7.51–7.44
(
3R,3aR)-3-((Trityloxy)methyl)-3a,4-dihydro-1H,3H-benzo (m, 6H), 7.36–7.30 (m, 6H), 7.28–7.22 (m, 3H), 6.58 (dd, J ¼ 2.8,
[
b]oxazolo[3,4-d][1,4]oxazin-1-one
(11c).
ꢁ
White
solid 8.8 Hz, 1H), 6.48 (d, J ¼ 2.8 Hz, 1H), 4.58–4.53 (m, 1H), 4.49 (dd, J
(
340 mg, 73% yield); mp: 249–251 C. The product was ¼ 1.6, 9.2 Hz, 1H), 4.06–3.93 (m, 2H), 3.73 (s, 3H), 3.56 (dd, J ¼
1
3
analyzed by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; 3.6, 10.4 Hz, 1H), 3.40 (dd, J ¼ 4.4, 10.4 Hz, 1H). C NMR (100
ꢀ1
eluent: hexane/isopropanol, 85/15; ow rate: 0.7 mL min ; l MHz, acetone-d ) d: 157.8, 154.9, 146.6, 144.7, 129.5, 128.9, 128.2,
6
ꢁ
¼
220 nm; T ¼ 20 C): t ¼ 20.17 min (100.00%). The enan- 121.4, 118.1, 108.3, 103.0, 87.8, 75.4, 67.0, 65.0, 55.9, 53.6. HR-MS
R
2
5
+
tiomeric purity of 11c was determined to be >99% ee. [a]
¼
(ESI): m/z [M + Na] calcd for C H NNaO : 516.1781; found:
31 27 5
D
1
ꢀ
32.6 (c ¼ 1, DMSO). H NMR (400 MHz, acetone-d
6
) d: 8.28– 516.1780.
(3R,3aS)-8-Methyl-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
8
.24 (m, 1H), 7.48–7.42 (m, 6H), 7.33–7.22 (m, 9H), 7.09–6.98
(
m, 2H), 6.95–6.90 (m, 1H), 5.06–5.00 (m, 1H), 4.56–4.49 (m, benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11ad). White solid
ꢁ
1
3
H), 4.40 (dd, J ¼ 3.2, 10.4 Hz, 1H), 4.11 (t, J ¼ 10.0 Hz, 1H), (388 mg, 81% yield); mp: 155–157 C. The product was analyzed
.60 (dd, J ¼ 4.4, 11.2 Hz, 1H), 3.09 (dd, J ¼ 2.8, 10.8 Hz, 1H). by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: hexane/
1
3
ꢀ1
C NMR (100 MHz, acetone-d ) d: 154.3, 145.2, 144.4, 129.4, isopropanol, 90/10; ow rate: 1 mL min ; l ¼ 220 nm; T ¼
6
ꢁ
1
6
C
28.9, 128.2, 125.6, 124.5, 122.5, 118.5, 117.9, 88.1, 74.6, 25 C): t ¼ 14.86 min (99.62%), t ¼ 20.00 min (0.38%). The
R
R
+
4.3, 63.0, 54.2. HR-MS (ESI): m/z [M + Na] calcd for enantiomeric purity of 11ad was determined to be 99.2% ee.
2
1
1
30
H
(
25NNaO
4
: 486.1676; found: 486.1666.
[a]
D
¼ ꢀ26.9 (c ¼ 1, CHCl
3 6
). H NMR (500 MHz, acetone-d ) d:
3S,3aS)-3-((Trityloxy)methyl)-3a,4-dihydro-1H,3H-benzo[b] 7.80 (s, 1H), 7.56–7.45 (m, 6H), 7.41–7.32 (m, 6H), 7.32–7.24 (m,
oxazolo[3,4-d][1,4]oxazin-1-one (11d). White solid (371 mg, 3H), 6.85 (d, J ¼ 9.0 Hz, 1H), 6.81 (d, J ¼ 9.0 Hz, 1H), 4.64–4.56
ꢁ
8
0% yield); mp: 250–252 C. The product was analyzed by (m, 1H), 4.47 (d, J ¼ 10.5 Hz, 1H), 4.13–4.04 (m, 1H), 3.97 (t, J ¼
chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: hexane/ 10.5 Hz, 1H), 3.60 (d, J ¼ 10.0 Hz, 1H), 3.46 (dd, J ¼ 3.5, 10.5 Hz,
ꢀ
1
13
isopropanol, 85/15; ow rate: 0.7 mL min ; l ¼ 220 nm; T 1H), 2.30 (s, 3H). C NMR (100 MHz, acetone-d ) d: 154.7, 144.7,
6
ꢁ
¼
20 C): t ¼ 21.88 min (100.00%). The enantiomeric purity of 143.6, 131.5, 129.5, 128.9, 128.2, 125.8, 124.5, 120.5, 117.4, 87.8,
R
2
5
+
1
1d was determined to be >99% ee. [a] ¼ +35.8 (c ¼ 1, 75.4, 67.2, 64.9, 53.9, 21.0. HR-MS (ESI): m/z [M + H] calcd for
D
1
DMSO). H NMR (400 MHz, acetone-d
6
) d: 8.28–8.24 (m, 1H),
31 4
C H28NO : 478.2013; found: 478.2005.
7
6
.48–7.42 (m, 6H), 7.33–7.22 (m, 9H), 7.09–6.98 (m, 2H), 6.95–
.90 (m, 1H), 5.06–5.00 (m, 1H), 4.56–4.49 (m, 1H), 4.40 (dd, J benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11ae). White solid
(3R,3aS)-7-Methyl-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
ꢁ
¼
3.2, 10.4 Hz, 1H), 4.11 (t, J ¼ 10.0 Hz, 1H), 3.60 (dd, J ¼ 4.4, (407 mg, 85% yield); mp: 237–239 C. The product was analyzed
1
3
1
1.2 Hz, 1H), 3.09 (dd, J ¼ 2.8, 10.8 Hz, 1H). C NMR (100 by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: hexane/
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ꢀ
1
isopropanol, 80/20; ow rate: 1 mL min ; l ¼ 220 nm; T ¼ 25 4.16–4.10 (m, 1H), 4.07 (t, J ¼ 9.6 Hz, 1H), 3.62 (dd, J ¼ 3.6,
ꢁ
13
C): tR ¼ 11.75 min (98.15%), t ¼ 14.16 min (1.85%). The 10.4 Hz, 1H), 3.46 (dd, J ¼ 4.4, 10.8 Hz, 1H). C NMR (100 MHz,
R
enantiomeric purity of 11ae was determined to be 96.3% ee. acetone-d ) d: 154.6, 146.6, 144.6, 129.5, 128.9, 128.2, 125.1,
6
2
1
1
[
a] ¼ ꢀ27.0 (c ¼ 1, CHCl ). H NMR (400 MHz, acetone-d ) d: 124.4, 121.7, 120.6, 116.7, 87.9, 75.7, 67.3, 64.8, 53.4. HR-MS
D
3
6
+
7
7
4
1
.81 (d, J ¼ 8.0 Hz, 1H), 7.52–7.46 (m, 6H), 7.39–7.31 (m, 6H), (ESI): m/z [M + Na] calcd for C30
4
H24BrNNaO : 564.0781;
.31–7.25 (m, 3H), 6.84–6.78 (m, 1H), 6.76 (d, J ¼ 0.8 Hz, 1H), found: 564.0772.
.62–4.56 (m, 1H), 4.50 (dd, J ¼ 2.8, 10.0 Hz, 1H), 4.10–4.03 (m,
(3R,3aS)-6-Bromo-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
H), 3.99 (t, J ¼ 10.0 Hz, 1H), 3.60 (dd, J ¼ 4.0, 10.4 Hz, 1H), 3.44 benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11ai). White solid
1
3
ꢁ
(
dd, J ¼ 4.4, 10.4 Hz, 1H), 2.26 (s, 3H). C NMR (100 MHz, (460 mg, 85% yield); mp: 213–215 C. The product was analyzed
acetone-d ) d: 154.8, 145.6, 144.7, 135.1, 129.5, 128.9, 128.2, by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: hexane/
6
ꢀ1
1
22.8, 122.3, 120.2, 118.0, 87.8, 75.4, 67.3, 64.9, 53.8, 21.0. HR- isopropanol, 95/5; ow rate: 1 mL min ; l ¼ 210 nm; T ¼ 25
+
ꢁ
MS (ESI): m/z [M + Na] calcd for C H NNaO : 500.1832;
found: 500.1808.
3R,3aS)-9-Bromo-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
C): tR ¼ 29.35 min (1.38%), t ¼ 31.89 min (98.62%). The
3
1
27
4
R
enantiomeric purity of 11ai was determined to be 97.2% ee.
2
1
1
(
[a]
D
¼ ꢀ34.8 (c ¼ 1, CHCl
3 6
). H NMR (400 MHz, acetone-d ) d:
benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11af). Off-white solid 7.98 (dd, J ¼ 1.6, 8.0 Hz, 1H), 7.55–7.46 (m, 6H), 7.40–7.32 (m,
ꢁ
(
427 mg, 79% yield); mp: 234–236 C. The product was analyzed 6H), 7.32–7.25 (m, 4H), 6.96 (t, J ¼ 8.0 Hz, 1H), 4.74–4.62 (m,
by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: hexane/ 2H), 4.24–4.09 (m, 2H), 3.63 (dd, J ¼ 3.6, 10.4 Hz, 1H), 3.46 (dd, J
ꢀ
1
13
isopropanol, 80/20; ow rate: 1 mL min ; l ¼ 210 nm; T ¼ ¼ 4.0, 10.4 Hz, 1H). C NMR (100 MHz, acetone-d ) d: 154.6,
6
ꢁ
2
5 C): tR ¼ 14.85 min (99.51%), t ¼ 19.54 min (0.49%). The 144.6, 142.9, 129.5, 128.9, 128.7, 128.2, 126.3, 122.8, 119.8,
R
+
enantiomeric purity of 11af was determined to be 99.0% ee. 111.1, 87.8, 75.4, 67.8, 64.8, 53.5. HR-MS (ESI): m/z [M + Na]
2
1
1
[a]
D
¼ ꢀ85.4 (c ¼ 1, CHCl
.59–7.51 (m, 6H), 7.39–7.31 (m, 6H), 7.31–7.24 (m, 4H), 7.11 (t, J
8.4 Hz, 1H), 6.94 (dd, J ¼ 1.6, 8.4 Hz, 1H), 4.64–4.54 (m, 2H), benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11aj). White solid
3
). H NMR (400 MHz, acetone-d
6
) d: calcd for C30
4
H24BrNNaO : 564.0781; found: 564.0757.
7
(3R,3aS)-8-Fluoro-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
¼
ꢁ
4
.04 (t, J ¼ 10.8 Hz, 1H), 3.99–3.93 (m, 1H), 3.62 (dd, J ¼ 3.6, (405 mg, 84% yield); mp: 180–182 C. The product was analyzed
13
1
0.8 Hz, 1H), 3.38 (dd, J ¼ 4.0, 10.8 Hz, 1H). C NMR (100 MHz, by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: hexane/
ꢀ
1
acetone-d ) d: 154.5, 149.6, 144.7, 129.6, 128.9, 128.3, 128.1, isopropanol, 90/10; ow rate: 1 mL min ; l ¼ 220 nm; T ¼
6
ꢁ
1
(
26.7, 123.8, 119.4, 117.0, 87.8, 75.5, 67.5, 64.8, 52.0. HR-MS 25 C): t ¼ 16.99 min (98.18%), t ¼ 19.75 min (1.82%). The
R
R
+
ESI): m/z [M + Na] calcd for C H BrNNaO : 564.0781; enantiomeric purity of 11aj was determined to be 96.4% ee.
30 24 4
2
1
1
found: 564.0778.
[a]
D
¼ ꢀ26.9 (c ¼ 1, CHCl
3 6
). H NMR (400 MHz, acetone-d ) d:
(
3R,3aS)-8-Bromo-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
7.76 (dd, J ¼ 3.2, 10.4 Hz, 1H), 7.54–7.47 (m, 6H), 7.40–7.32 (m,
benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11ag). Pink solid 6H), 7.32–7.26 (m, 3H), 6.95 (dd, J ¼ 5.2, 8.8 Hz, 1H), 6.84–6.78
ꢁ
(
454 mg, 84% yield); mp: 207–209 C. The product was analyzed (m, 1H), 4.68–4.62 (m, 1H), 4.54 (dd, J ¼ 3.2, 10.4 Hz, 1H), 4.18–
by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: hexane/ 4.10 (m, 1H), 4.02 (t, J ¼ 10.4 Hz, 1H), 3.62 (dd, J ¼ 4.0, 10.8 Hz,
ꢀ
1
13
isopropanol, 90/10; ow rate: 1 mL min ; l ¼ 210 nm; T ¼ 1H), 3.48 (dd, J ¼ 4.4, 10.4 Hz, 1H). C NMR (100 MHz, acetone-
ꢁ
2
5 C): tR ¼ 16.33 min (97.61%), t ¼ 21.17 min (2.39%). The d ) d: 157.8 (d, J ¼ 235 Hz), 154.6, 144.6, 141.9 (d, J ¼ 3 Hz),
R
6
enantiomeric purity of 11ag was determined to be 95.2% ee. 129.5, 128.9, 128.2, 125.4 (d, J ¼ 12 Hz), 118.6 (d, J ¼ 9 Hz), 111.4
2
1
1
[a]
D
¼ ꢀ9.0 (c ¼ 1, CHCl
3
). H NMR (400 MHz, acetone-d
6
) d: (d, J ¼ 24 Hz), 106.6 (d, J ¼ 28 Hz), 87.9, 75.8, 67.0, 64.7, 53.7.
+
8
7
8
4
1
.14 (d, J ¼ 2.4 Hz, 1H), 7.53–7.46 (m, 6H), 7.40–7.32 (m, 6H), HR-MS (ESI): m/z [M + Na] calcd for C30
4
H24FNNaO : 504.1582;
.32–7.25 (m, 3H), 7.18 (dd, J ¼ 2.8, 8.8 Hz, 1H), 6.91 (d, J ¼ found: 504.1570.
.8 Hz, 1H), 4.69–4.63 (m, 1H), 4.57 (dd, J ¼ 3.2, 10.4 Hz, 1H),
(3R,3aS)-7-Fluoro-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
.18–4.11 (m, 1H), 4.06 (t, J ¼ 10.4 Hz, 1H), 3.62 (dd, J ¼ 4.0, benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11ak). White solid
1
3
ꢁ
0.8 Hz, 1H), 3.48 (dd, J ¼ 4.4, 10.4 Hz, 1H). C NMR (100 MHz, (412 mg, 86% yield); mp: 178–180 C. The product was analyzed
acetone-d ) d: 154.6, 145.0, 144.6, 129.5, 128.9, 128.2, 127.8, by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: hexane/
6
ꢀ
1
1
26.3, 122.5, 119.6, 113.5, 87.9, 75.8, 67.1, 64.7, 53.4. HR-MS isopropanol, 90/10; ow rate: 0.7 mL min ; l ¼ 210 nm; T ¼
+
ꢁ
(
ESI): m/z [M + Na] calcd for C30
found: 564.0756.
3R,3aS)-7-Bromo-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
H24BrNNaO
4
: 564.0781; 25 C): t
R
¼ 23.65 min (97.54%), t ¼ 25.39 min (2.46%). The
R
enantiomeric purity of 11ak was determined to be 95.1% ee.
2
1
1
(
[a]
D
¼ ꢀ29.5 (c ¼ 1, CHCl
3 6
). H NMR (400 MHz, acetone-d ) d:
benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11ah). White solid 7.94 (dd, J ¼ 5.6, 8.8 Hz, 1H), 7.54–7.45 (m, 6H), 7.41–7.32 (m,
ꢁ
(
478 mg, 88% yield); mp: 208–210 C. The product was analyzed 6H), 7.32–7.24 (m, 3H), 6.87–6.78 (m, 1H), 6.74 (dd, J ¼ 2.8,
by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: hexane/ 10.0 Hz, 1H), 4.67–4.60 (m, 1H), 4.60–4.53 (m, 1H), 4.16–4.00
ꢀ
1
isopropanol, 90/10; ow rate: 0.6 mL min ; l ¼ 210 nm; T ¼ (m, 2H), 3.61 (dd, J ¼ 4.0, 10.8 Hz, 1H), 3.45 (dd, J ¼ 4.4, 10.8 Hz,
ꢁ
13
2
5 C): tR ¼ 27.91 min (2.21%), t ¼ 29.96 min (97.79%). The 1H). C NMR (100 MHz, acetone-d ) d: 160.1 (d, J ¼ 240 Hz),
R
6
enantiomeric purity of 11ah was determined to be 95.6% ee. 154.9, 146.7 (d, J ¼ 12 Hz), 144.6, 129.5, 128.9, 128.2, 121.6 (d, J
2
1
1
[a]
D
¼ ꢀ12.9 (c ¼ 1, CHCl
3
). H NMR (400 MHz, acetone-d
6
) d: ¼ 10 Hz), 121.4 (d, J ¼ 2 Hz), 108.8 (d, J ¼ 22 Hz), 104.9 (d, J ¼ 26
+
7
7
2
.90 (d, J ¼ 8.8 Hz, 1H), 7.52–7.47 (m, 6H), 7.39–7.32 (m, 6H), Hz), 87.8, 75.5, 67.5, 64.9, 53.3. HR-MS (ESI): m/z [M + Na] calcd
.32–7.25 (m, 3H), 7.18 (dd, J ¼ 2.0, 8.4 Hz, 1H), 7.13 (d, J ¼ for C30
4
H24FNNaO : 504.1582; found: 504.1578.
.4 Hz, 1H), 4.68–4.63 (m, 1H), 4.57 (dd, J ¼ 2.4, 9.6 Hz, 1H),
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(
3R,3aS)-6,8-Dichloro-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H- enantiomeric purity of 11ao was determined to be >99% ee.
2
1
1
benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11al). Off-white solid [a]
¼ +5.3 (c ¼ 1, CHCl
). H NMR (500 MHz, acetone-d ) d:
3 6
D
ꢁ
(
449 mg, 85% yield); mp: 205–207 C. The product was 8.88 (d, J ¼ 2.0 Hz, 1H), 7.97 (dd, J ¼ 2.5, 9.0 Hz, 1H), 7.55–
analyzed by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: 7.46 (m, 6H), 7.40–7.32 (m, 6H), 7.32–7.24 (m, 3H), 7.17 (d, J ¼
ꢀ1
hexane/isopropanol, 90/10; ow rate: 1 mL min ; l ¼ 210 nm; 9.0 Hz, 1H), 4.78–4.67 (m, 2H), 4.30–4.19 (m, 2H), 3.66 (dd, J ¼
ꢁ
13
T ¼ 25 C): t ¼ 12.24 min (98.95%), t ¼ 14.46 min (1.05%). 3.5, 10.5 Hz, 1H), 3.55 (dd, J ¼ 4.5, 10.5 Hz, 1H). C NMR (100
R
R
The enantiomeric purity of 11al was determined to be 97.9% MHz, acetone-d
6
) d: 154.6, 151.0, 144.6, 142.7, 129.5, 128.9,
2
D
1
1
ee. [a] ¼ ꢀ15.1 (c ¼ 1, CHCl ). H NMR (500 MHz, acetone-d ) 128.3, 125.2, 120.8, 118.3, 115.6, 88.0, 76.0, 67.7, 64.7, 53.0.
3
6
+
24 2 6
d: 7.99 (s, 1H), 7.55–7.45 (m, 6H), 7.42–7.32 (m, 6H), 7.32–7.24 HR-MS (ESI): m/z [M + Na] calcd for C30H N NaO :
(
(
m, 3H), 7.21 (s, 1H), 4.77–4.65 (m, 2H), 4.29–4.10 (m, 2H), 3.64 531.1527; found: 531.1525.
1
3
dd, J ¼ 3.5, 10.5 Hz, 1H), 3.50 (dd, J ¼ 4.0, 10.5 Hz, 1H).
C
(3R,3aS)-7-Nitro-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
) d: 154.4, 144.6, 141.0, 129.5, 128.9, benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11ap). Yellow solid
NMR (100 MHz, acetone-d
6
ꢁ
1
5
5
28.2, 127.1, 126.2, 124.9, 123.1, 118.4, 88.0, 75.8, 67.6, 64.6, (374 mg, 74% yield); mp: 220–222 C. The product was
+
3.3. HR-MS (ESI): m/z [M + Na] calcd for C H Cl NNaO : analyzed by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm;
3
0
23
2
4
ꢀ
1
54.0896; found: 554.0880.
3R,3aS)-7,8-Diuoro-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
eluent: hexane/isopropanol, 60/40; ow rate: 1 mL min ; l ¼
ꢁ
(
210 nm; T ¼ 25 C): t
R
¼ 21.46 min (100.00%). The enantio-
2
1
benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11am). White solid meric purity of 11ap was determined to be >99% ee. [a]
D
¼
ꢁ
1
(
413 mg, 83% yield); mp: 222–224 C. The product was analyzed +34.0 (c ¼ 1, CHCl
). H NMR (400 MHz, acetone-d ) d: 8.23 (d,
3 6
by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; eluent: hexane/ J ¼ 8.8 Hz, 1H), 7.94 (dd, J ¼ 2.8, 10.2 Hz, 1H), 7.78 (d, J ¼
ꢀ
1
isopropanol, 90/10; ow rate: 0.7 mL min ; l ¼ 210 nm; T ¼ 2.8 Hz, 1H), 7.53–7.48 (m, 6H), 7.39–7.33 (m, 6H), 7.32–7.26
ꢁ
2
5 C): t
R
¼ 20.21 min (98.59%), t
¼ 22.95 min (1.40%). The (m, 3H), 4.78–4.72 (m, 1H), 4.68 (dd, J ¼ 2.8, 10.4 Hz, 1H),
R
enantiomeric purity of 11am was determined to be 97.2% ee. 4.31–4.24 (m, 1H), 4.19 (t, J ¼ 10.4 Hz, 1H), 3.67 (dd, J ¼ 3.6,
2
1
1
13
[
a] ¼ ꢀ24.6 (c ¼ 1, CHCl ). H NMR (400 MHz, acetone-d ) d: 10.4 Hz, 1H), 3.52 (dd, J ¼ 4.4, 10.8 Hz, 1H). C NMR (100
D
3
6
7
6
.88 (dd, J ¼ 8.4, 12.0 Hz, 1H), 7.52–7.47 (m, 6H), 7.39–7.32 (m, MHz, DMSO-d
6
) d: 153.3, 144.1, 143.2, 142.9, 129.8, 128.2,
H), 7.32–7.25 (m, 3H), 6.96 (dd, J ¼ 7.6, 11.6 Hz, 1H), 4.70–4.63 128.0, 127.2, 118.6, 116.9, 112.1, 86.3, 74.9, 65.7, 63.4, 51.8.
+
(
m, 1H), 4.58 (dd, J ¼ 2.8, 10.4 Hz, 1H), 4.17–4.10 (m, 1H), 4.06 (t, HR-MS (ESI): m/z [M + Na] calcd for C30
H N NaO :
24 2 6
J ¼ 10.4 Hz, 1H), 3.62 (dd, J ¼ 3.6, 10.4 Hz, 1H), 3.47 (dd, J ¼ 4.4, 531.1527; found: 531.1524.
1
3
1
0.4 Hz, 1H). C NMR (100 MHz, DMSO-d
6
) d: 153.7, 145.5 (dd, J
(3R,3aS)-7-(3-Oxomorpholino)-3-((trityloxy)methyl)-3a,4-dihy-
¼
13, 240 Hz), 143.5 (dd, J ¼ 13, 237 Hz), 143.2, 140.7 (dd, J ¼ 2, dro-1H,3H-benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11aq). Off-
ꢁ
1
0 Hz), 128.2, 128.0, 127.2, 119.6 (dd, J ¼ 3, 9 Hz), 107.2 (d, J ¼ 23 white solid (1.6 g, 62% yield). Mp: 211–213 C. The product
Hz), 106.0 (d, J ¼ 21 Hz), 86.2, 74.6, 65.8, 63.6, 51.5. HR-MS (ESI): was analyzed by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm;
+
ꢀ1
m/z [M + Na] calcd for C H F NNaO : 522.1487; found: eluent: hexane/ethyl acetate, 50/50; ow rate: 0.5 mL min ; l
3
0
23
2
4
ꢁ
5
22.1474.
(
¼ 254 nm; T ¼ 25 C): t
R
¼ 26.30 min (100.00%). The enan-
2
5
3R,3aS)-7-Bromo-8-uoro-3-((trityloxy)methyl)-3a,4-dihy- tiomeric purity of 11aq was determined to be >99% ee. [a]
¼
D
1
dro-1H,3H-benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11an). ꢀ11.6 (c ¼ 1, CHCl
). H NMR (400 MHz, DMSO-d ) d: 7.85 (d, J
6
3
ꢁ
Off-white solid (185 mg, 81% yield); mp: 221–223 C. The ¼ 9.2 Hz, 1H), 7.54–7.19 (m, 15H), 7.16–6.91 (m, 2H), 4.66–4.57
product was analyzed by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 (m, 1H), 4.53–4.42 (m, 1H), 4.18 (s, 2H), 4.05–3.90 (m, 4H), 3.70
ꢀ
1
mm; eluent: hexane/isopropanol, 80/20; ow rate: 1 mL min
;
(t, J ¼ 5.2 Hz, 2H), 3.48 (dd, J ¼ 3.2, 10.8 Hz, 1H), 3.37–3.25 (m,
ꢁ
13
l ¼ 210 nm; T ¼ 25 C): t ¼ 9.87 min (100.00%). The enan- 1H). C NMR (100 MHz, DMSO-d
6
) d: 165.9, 153.8, 144.3,
R
2
1
tiomeric purity of 11an was determined to be >99% ee. [a]
¼
143.3, 137.8, 128.2, 128.0, 127.2, 121.6, 119.2, 118.4, 114.2,
). H NMR (500 MHz, acetone-d
3 6
) d: 7.88 (d, J 86.2, 74.4, 67.7, 65.9, 63.6, 63.4, 51.9, 49.0. HR-MS (ESI): m/z [M
D
1
ꢀ
9.7 (c ¼ 1, CHCl
+
¼
10.0 Hz, 1H), 7.55–7.41 (m, 6H), 7.41–7.32 (m, 6H), 7.32–7.25 + H] calcd for C34
H N O : 563.2177; found: 563.2201.
31 2 6
(
m, 3H), 7.22 (d, J ¼ 6.5 Hz, 1H), 4.74–4.63 (m, 1H), 4.57 (dd, J
¼
3.0, 10.5 Hz, 1H), 4.22–4.11 (m, 1H), 4.06 (t, J ¼ 10.5 Hz, 1H),
Gram-scale synthesis and application
3
.63 (dd, J ¼ 4.0, 11.0 Hz, 1H), 3.49 (dd, J ¼ 4.0, 10.5 Hz, 1H).
1
3
C NMR (100 MHz, acetone-d ) d: 154.4, 154.2 (d, J ¼ 236 Hz),
(3R,3aS)-7-Bromo-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H-
6
1
44.6, 142.6 (d, J ¼ 2 Hz), 129.5, 128.9, 128.2, 125.2 (d, J ¼ 10 benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11ah). Compound
Hz), 121.6, 107.4 (d, J ¼ 30 Hz), 102.6 (d, J ¼ 23 Hz), 88.0, 76.0, 11ah was prepared from 8i (1.4 g, 4.36 mmol) and compound 9a
+
6
7.1, 64.6, 53.4. HR-MS (ESI): m/z [M + Na] calcd for C30
H
23
-
(2.0 g, 5.89 mmol) following the general procedure. Aer
BrFNNaO
4
: 582.0687; found: 582.0682.
workup, MeOH was added to the residue. The mixture was
(
3R,3aS)-8-Nitro-3-((trityloxy)methyl)-3a,4-dihydro-1H,3H- stirred for 1 h, and then the slurry was ltered, the lter cake
benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (11ao). Yellow solid was washed with MeOH to give the product (1.7 g, 74%) as an
ꢁ
(
405 mg, 80% yield); mp: 235–237 C. The product was off-white solid. The product was analyzed by chiral HPLC (IC, 5
analyzed by chiral HPLC (IC, 5 mm, 4.6 mm ꢂ 250 mm; mm, 4.6 mm ꢂ 250 mm; eluent: hexane/isopropanol, 90/10; ow
ꢀ
1
ꢀ1
ꢁ
eluent: hexane/isopropanol, 60/40; ow rate: 1 mL min ; l ¼ rate: 0.6 mL min ; l ¼ 210 nm; T ¼ 25 C): t
¼ 29.71 min
R
ꢁ
2
10 nm; T ¼ 25 C): tR ¼ 20.31 min (100.00%). The (100.00%). The enantiomeric purity of 11ah was determined to
be >99% ee.
This journal is © The Royal Society of Chemistry 2020
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3R,3aS)-7-Bromo-3-(hydroxymethyl)-3a,4-dihydro-1H,3H-
Paper
(
Technology Major Project of China (no. 2015ZX09102007-013)
benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one (12). To a solution of are greatly appreciated.
compound 11ah (1.6 g, 3 mmol) in MeOH (1.6 mL) and DCM (16
mL) was added TsOH$H O (1.14 g, 6 mmol). The reaction
2
mixture was stirred at room temperature for 4 h. Saturated
Notes and references
NaHCO (6 mL) was added and stirred vigorously for 10 min.
3
The mixture was extracted with DCM. The combined organic
layer was dried over anhydrous Na SO and concentrated in
1 K. J. Shaw and M. R. Barbachyn, Ann. N. Y. Acad. Sci, 2011,
1241, 48.
2
4
vacuum. The residue was stirred in a mixture of DCM (10 mL)
and PE (10 mL) for 10 min. Aer ltration, the lter cake was
dried to give compound 12 (0.8 g, 89%) as an off-white solid.
2 W. B. Im, S. H. Choi, J.-Y. Park, S. H. Choi, J. Finn and
S.-H. Yoon, Eur. J. Med. Chem., 2011, 46, 1027.
3 S. Roehrig, A. Straub, J. Pohlmann, T. Lampe,
J. Pernerstorfer, K.-H. Schlemmer, P. Reinemer and
E. Perzborn, J. Med. Chem., 2005, 48, 5900.
ꢁ
25
1
Mp: 148–150 C; [a]
MHz, CDCl
D
¼ ꢀ25.4 (c ¼ 0.22, DMSO). H NMR (400
3
) d: 7.89 (dd, J ¼ 1.6, 8.0 Hz, 1H), 7.15–7.09 (m, 2H),
4
1
1
1
.50 (dd, J ¼ 3.2, 10.4 Hz, 1H), 4.41–4.33 (m, 1H), 4.22–4.12 (m,
4 (a) Q.-S. Xin, H.-X. Fan, B. Guo, H.-L. He, S. Gao, H. Wang,
Y. Q. Huang and Y.-S. Yang, J. Med. Chem., 2011, 54, 7493;
(b) B. Guo, H.-X. Fan, Q.-S. Xin, W.-J. Chu, H. Wang and
Y.-S. Yang, Bioorg. Med. Chem. Lett., 2013, 23, 3697; (c)
B. Guo, H.-X. Fan, Q.-S. Xin, W.-J. Chu, H. Wang,
Y.-Q. Huang, X.-Y. Chen and Y.-S. Yang, J. Med. Chem.,
2013, 56, 2642.
5 (a) T. Xue, S. Ding, B. Guo, Y.-R. Zhou, P. Sun, H.-Y. Wang,
W.-J. Chu, G.-Q. Gong, Y.-Y. Wang, X.-Y. Chen and
Y.-S. Yang, J. Med. Chem., 2014, 57, 7770; (b) C. Xu and
Y.-J. Ren, Bioorg. Med. Chem. Lett., 2015, 25, 4522.
6 H.-Y. Zhao, Y. Lu, L. Sheng, Z.-S. Yuan, B. Wang, W.-P. Wang,
Y. Li, C. Ma, X.-L. Wang, D.-F. Zhang and H.-H. Huang, ACS
Med. Chem. Lett., 2017, 8, 533.
H), 4.03 (dd, J ¼ 4.0, 12.4 Hz, 1H), 3.96–3.82 (m, 2H), 2.18 (brs,
1
3
H). C NMR (100 MHz, CDCl ) d: 153.4, 144.9, 125.0, 122.2,
3
20.4, 120.2, 117.0, 75.9, 66.6, 62.1, 52.1. HR-MS (ESI): m/z [M +
+
H] calcd for C11
H
11BrNO
4
: 299.9866; found: 299.9876.
(
3R,3aS)-3-(Hydroxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-3a,4-dihydro-1H,3H-benzo[b]oxazolo[3,4-
d][1,4]oxazin-1-one (13). To a mixture of compound 12
(
100 mg, 0.33 mmol), bis(pinacolato)diboron (168 mg, 0.66
mmol), KOAc (98 mg, 1 mmol) and Pd(dppf)Cl $CH Cl (14
2
2
2
mg) was added DMSO (3 mL) under argon. The reaction
ꢁ
mixture was heated at 85 C for 2.5 h. The mixture was cooled
to room temperature and water was added. The resulting
mixture was extracted with ethyl acetate and the organic
phase was washed with water and brine, dried over anhy-
7 K. C. Nicolaou, P. S. Baran, Y.-L. Zhong and K. Sugita, J. Am.
Chem. Soc., 2002, 124, 2212.
2 4
drous Na SO , ltered and the ltrate was concentrated in
vacuo. The residue was puried by chromatography on silica
gel eluted with EtOAc/PE (1 : 1) to give 13 (91 mg, 80%) as
8 Y.-J. Cui, Y.-X. Dang, Y.-S. Yang and R.-Y. Ji, J. Heterocycl.
Chem., 2006, 43, 1071.
ꢁ
1
a white solid. Mp: 184–186 C. H NMR (400 MHz, CDCl ) d:
9 S.-H. Chen, Z.-Z. Ding, G.-L. Gong, X.-B. Yan, W. Huang,
F. Guo, B.-L. Duan, R.-L. Gao, P.-F. Zhou, X.-H. Lu and
G.-M. Dong, CN Pat., 105503903B, New Drug Research and
Development Co., Ltd. of North China Pharmaceutical
Corporation, 2019.
3
8
.02 (d, J ¼ 8.0 Hz, 1H), 7.43 (dd, J ¼ 1.2, 8.0 Hz, 1H), 7.40 (d, J
1.2 Hz, 1H), 4.48 (dd, J ¼ 3.2, 10.4 Hz, 1H), 4.39–4.32 (m,
H), 4.23–4.15 (m, 1H), 4.02 (dd, J ¼ 3.6, 12.4 Hz, 1H), 3.95–
¼
1
3
1
5
1
3
3
.81 (m, 2H), 1.34 (s, 12H). C NMR (100 MHz, CDCl ) d:
53.3, 143.6, 128.4, 125.6, 123.1, 118.3, 83.9, 76.0, 66.4, 62.1, 10 R. Malhotra, T. K. Dey, S. Basu and S. Hajra, Org. Biomol.
+
2.5, 24.9, 24.8. HR-MS (ESI): m/z [M + H] calcd for
Chem., 2015, 13, 3211.
C17H23BNO : 348.1613; found: 348.1630.
11 H.-H. Huang, D.-F. Zhang and H.-Y. Zhao, WO Pat.,
6
2018177302A1, Institute of Materia Medica, Chinese
Academy of Medical Sciences, 2018.
2 A. Berger and K. D. Wehrstedt, J. Loss Prev. Process Ind., 2010,
23, 734.
Conflicts of interest
1
1
1
There are no conicts to declare.
3 M. R. Barbachyn and C. W. Ford, Angew. Chem., Int. Ed.,
2003, 42, 2010.
Acknowledgements
4 P. Chen, Y.-Y. Zhang, C.-H. Shi, X. Meng, Y.-S. Yang,
Financial supports from the National Natural Science Founda-
tion of China (no. 81502917) and the National Science &
X.-L. Zhou and B. Guo, J. Chem. Res., 2019, 43, 380.
24044 | RSC Adv., 2020, 10, 24037–24044
This journal is © The Royal Society of Chemistry 2020