Enantiopure synthesis of dihydrobenzo[1,4]-oxazine-3-carboxylic acids and a route to benzoxazinyl oxazolidinones

Article abstract of DOI:10.1039/c4ob02475c

A two step protocol is developed for the efficient synthesis of enantiopure N-Boc-dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids 4 from serine derived cyclic sulfamidate via intramolecular arylamination. The RuPhos Palladacycle along with additional RuPhos ligand is found to be an efficient catalyst for the arylamination of β-(2-bromoaryloxy)amino acids 3 to provide easy and direct access to a variety of dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids 4 with complete retention of enantiopurity in moderate to high yields. Dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids are not only important unnatural amino acids, but are key precursors for the synthesis of important compounds such as benzoxazinyl oxazolidinones. A general approach for the synthesis of benzoxazinyl oxazolidinone is presented. This journal is

Full text of DOI:10.1039/c4ob02475c

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Enantiopure synthesis of dihydrobenzo[1,4]-
oxazine-3-carboxylic acids and a route to
Cite this: DOI: 10.1039/c4ob02475c
benzoxazinyl oxazolidinones†
Rajesh Malhotra,a Tushar K. Dey,a,b Sourav Basu*b and Saumen Hajra*c,d
A two step protocol is developed for the efficient synthesis of enantiopure N-Boc-dihydrobenzo[b]-1,4-
oxazine-3-carboxylic acids 4 from serine derived cyclic sulfamidate via intramolecular arylamination. The
RuPhos Palladacycle along with additional RuPhos ligand is found to be an efficient catalyst for the aryl-
amination of β-(2-bromoaryloxy)amino acids 3 to provide easy and direct access to a variety of dihydro-
benzo[b]-1,4-oxazine-3-carboxylic acids 4 with complete retention of enantiopurity in moderate to high
yields. Dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids are not only important unnatural amino acids, but
are key precursors for the synthesis of important compounds such as benzoxazinyl oxazolidinones.
A general approach for the synthesis of benzoxazinyl oxazolidinone is presented.
Received 25th November 2014,
Accepted 16th January 2015
DOI: 10.1039/c4ob02475c
www.rsc.org/obc
Introduction
Chiral 3-substituted dihydrobenzo[b]-1,4-oxazines are key
structural units of many bioactive natural products and phar-
maceuticals.1,2 These are also utilized as chiral catalysts in
asymmetric transfer hydrogenation.3 Thus several methods
have been developed for the non-racemic synthesis of
dihydrobenzoxazines.4–6 Among these, catalytic asymmetric
reduction of prochiral 1,4-benzoxazines has progressed and
matured sufficiently with excellent enantioselectivity, but
mostly for 3-aryl benzoxazines.4,5 Intramolecular Buchwald–
Hartwig arylamination7 of the β-aryloxyamines is an efficient
alternative protocol, as aryloxyamines can be obtained in large
quantities in optically pure form. Gallagher et al. reported Pd-
catalyzed intramolecular arylamination for the synthesis of
enantiopure 1,4-dihydrobenzoxazines and the Das group has
Scheme 1
efficiently replaced the palladium with
a Cu catalyst
(Scheme 1).6 Recently benz[b]-1,4-oxazine-3-carboxylic acids 4
and their derivatives have been found to be the fundamental
moiety of many potential drugs.8 These are also important
unnatural amino acids and could be precursors in the syn-
thesis of bio-active benzoxazinyl compounds (Fig. 1).9,10 Intra-
molecular arylamination of β-(2-haloaryloxy)amino acids 3 can
lead to dihydrobenzoxazine-3-carboxylic acids 4 (Scheme 1).
Surprisingly, none of the above methods describe the synthesis
of benzoxazine carboxylic acids or derivatives, maybe because
there was no suitable method for the synthesis of β-(2-haloaryl-
oxy)amino acids. To the best of our knowledge, there is no
other report on the synthesis of benz[b]-1,4-oxazine-3-car-
boxylic acids in optically pure form. Recently we have develo-
ped an efficient protocol for the direct synthesis of N-protected
aDepartment of Chemistry, Guru Jambheshwar University of Science and Technology,
Hisar, Haryana 125001, India
bTCG Life Sciences Ltd, Saltlake, Kolkata 700091, India.
E-mail: sourav@chembiotek.com; Fax: (+91)-33-23673058; Tel: (+91)-33-23673151
cCentre of Biomedical Research, SGPGIMS Campus, Lucknow 226014, India.
E-mail: saumen.hajra@cbmr.res.in
dDepartment of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur
721302, India. E-mail: shajra@chem.iitkgp.ernet.in; Fax: (+91)-3222-282252;
Tel: (+91)-3222-283340
†Electronic supplementary information (ESI) available: 1H- and 13C NMR spectra
and LC-MS for compounds 3, 4, 10a, 12a–14a, 18a, 20a and 21a and HPLC chro-
matograms of compounds 3a, 3c, 4a, 4c, 12a, 14a, 18a and 20a. See DOI:
10.1039/c4ob02475c
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β-aryloxyamino acids from cyclic sulfamidate carboxylic acid
derived from serine.11 This prompted us to study the arylami-
nation of β-(2-haloaryloxy)amino acids. Herein we report
RuPhos Palladacycle-catalyzed efficient intramolecular arylami-
nation of the β-(2-bromoaryloxy)amino acids for the enantio-
pure synthesis of N-Boc-benzo[b]-1,4-oxazine-3-carboxylic acids
4 and a general approach for the synthesis of benzoxazinyl oxa-
zolidinones 5.
Results and discussion
For the screening of the arylamination catalysts (Table 1), β-(2-
bromophenyloxy)amino acid 3a was taken as a model sub-
strate, and was prepared by the regioselective ring opening of
cyclic sulfamidate 6 with 2-bromophenol 7a at 0 °C following
our previously-developed method.11 Substrate 3a was heated in
the presence of Pd(OAc)2 under the conditions reported by the
Gallagher group. It showed >90% disappearance of substrate
3a but only traces of product 4a (<5%) detected by LC-MS
(Table 1; entry 1) and there was no improvement by changing
the solvent to dioxane (entry 2). The CuI-mediated reaction of
substrate 3a showed 40% conversion after 15 h giving a
1 : 1 mixture of the desired cyclized product 4a and des-bromo
product 8 along with other unidentified compounds (entry 3).
PEPPSI-IPr was also found to be ineffective towards arylamina-
tion of 3a (entry 4). We then screened the commonly-used
Buchwald–Hartwig arylamination catalyst Pd2(dba)3 in the
Fig. 1 Dihydrobenzoxazine-3-carboxylic acid 4 and some important
bioactive benzoxazinyl compounds.
Table 1 Screening of catalysts and reaction conditions for the intramolecular Buchwald–Hartwig coupling of 3a
Entry
Catalyst (mol%)
Ligand (mol%)
Solvent
T (°C)
Conv.a (%)
4a : 8b
Yieldc of 4a
1
2
3
4
5
6
7
8
Pd(OAc)2 (5)
Pd(OAc)2 (5)
CuI (5)
PEPPSI-IPr (2)
Pd2(dba)3 (15)
Pd2(dba)3 (15)
Pd2(dba)3 (15)
Pd2(dba)3 (15)
Xantphos (7.5)
Xantphos (7.5)
DMEDA (5)
—
BINAPH (15)
SPhos
XPhos
BrettPhos
RuPhos
Toluene
Dioxane
THF
100
100
80
100
100
100
100
100
100
60
100
60
100
100
100
100
100
>90
>90
40
30
60
100
100
100
100
70
100
60
100
100
100
75
ND
<5a
<5a
<10a
—
ND
1 : 1a
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
6 : 1a
54 : 46
80 : 20
83 : 17
95 : 5
96 : 4
85 : 15
98 : 2
97 : 3
>99 : 1
>99 : 1
>99 : 1
98 : 2
10 : 1
—
85
79
73
76
74
72
—
76
76
76
60
—
9
Pd2(dba)3 (15)
Pd2(dba)3 (15)
10
11
12
13
14
15
16
17
BrettPhos
—
RuPhos Palladacycle (15)
RuPhos Palladacycle (15)
RuPhos Palladacycle (15)
RuPhos Palladacycle (10)
RuPhos Palladacycle (5)
RuPhos Palladacycle (2)
RuPhos Palladacycle (1)
RuPhos (15)
RuPhos (15)
RuPhos (10)
RuPhos (5)
RuPhos (2)
RuPhos (1)
<25
a Determined by LC-MS. b Determined by 1H NMR of crude reaction mixture unless otherwise noted. c Combined isolated yield of 4a and 8 unless
otherwise noted.
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Table 2 Enantiopure synthesis of dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids 4a
Entry
1
ArOH
7
Amino acid 3
Dihydrobenzoxazine 4
7a
2
3
7b
7c
4
7d
5
6
7
7e
7f
7g
8
7h
7i
9
10
7j
NR
11
7k
a For the synthesis of dihydrobenzo[b]-1,4-oxazine-3-carboxylic acids 4, intramolecular arylamination (Buchwald–Hartwig coupling) of 3 was
carried out using RuPhos Palladacycle (5 mol%) and RuPhos (5 mol%) as a catalyst with Cs2CO3 in dioxane at 100 °C.
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presence of different commercially available ligands (entries conditions gave traces of desired product 11a. The poor solubi-
5–10). Among these, BrettPhos and RuPhos were found to be lity of the amino acid 10a in dioxane could be the cause of the
efficient systems providing high selectivity and yields towards failure of the reaction. Other solvents such as DMF, t-BuOH
arylamination over the des-bromo product (entries 8 and 9). and a combination of mixed solvents were screened for
Difficulties in the removal of minor des-bromo by-product 8 the aminoarylation of 10a. DMF was found to be a suitable
led us to look for a more efficient catalyst. We are delighted solvent for aminoarylation of 10a in the presence of RuPhos
to report that RuPhos Palladacycle was found to be a very Palladacycle and RuPhos at 100 °C and showed 20–30% of the
efficient catalyst and provided very high selectivity towards desired cyclized product mass (m/z) 11a in LC-MS. When
arylamination over the des-bromo by-product (98 : 2; entry 11). the reaction was carried out under microwave conditions, it
Further optimization using additional RuPhos ligand gave rise showed 60–80% of N-PMB-benzoxazine 11a in LC-MS. Surpris-
to excellent selectivity (>99 : 1) towards cyclized product 4a ingly, the compound 11a could not be isolated in pure form by
with very good isolated yield (76%; entry 13). The optimum silica-gel column chromatography and was found to be decom-
catalyst loading was found to be 5 mol% without any loss of posed on the silica gel, leading to a complex mixture of
yield and selectivity with complete retention of enantiopurity products.
(entry 15). Further lowering the catalyst loading (entries 16 and
17) and the reaction temperature (entries 10 and 12) led to
poor conversion and selectivity.
After standardization of the intramolecular arylamination
conditions, the method was generalized with different sub-
strates. For this purpose, a number of 2-bromophenols were
reacted with N-Boc-cyclic sulfamidate 6 providing moderate to
good yields of β-aryloxyamino acids 3, which were heated in
dioxane in the presence of RuPhos Palladacycle along with the
RuPhos ligand under standardized conditions (Table 2). All
the substrates 3 except substrates 3j and 3k underwent smooth
arylamination and gave very good yields of the desired dihy-
drobenzoxazin-3-carboxylic acids 4 with complete preservation
of enantiopurity (e.g. Table 2; entries 1 and 3). The moderate
yield of dihydronaphthoxazin-2-carboxylic acid 3k (entry 11),
might be due to the steric effect of the peri-hydrogen and the
lack of reaction with substrate 3j (entry 10), might be due to
the ortho-steric effect.
Similarly N-PMB protected serine sulfamidate carboxylic
acid 9 can provide N-PMB protected benzoxazine carboxylic
acid 11 in two steps (Scheme 2). In the first step, the regio-
selective ring opening of 9 afforded a very good yield of N-
PMB-β-(2-bromophenyloxy)amino acid 10a. However, intra-
molecular aminoarylation of 10a under the above optimized
Scheme 2 Synthesis of N-PMB-benzoxazine carboxylic acid 11a.
Scheme 3 Asymmetric synthesis of benzoxazinyl oxazolidinone 21.
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Functional modifications of the carboxylic acid group of synthesis of enantiopure dihydrobenzoxazine-3-carboxylic
benzoxazine-3-carboxylic acids 4 can lead to the synthesis of a acids and benzoxazinyl oxazolidinones.
wide variety of important bioactive compounds; for example,
We thank DBT (BIPP), New Delhi (sanction no.: 102/IFD/
benzoxazinyl oxazolidinones 5. Reduction of compound 4a SAN/1191/2009–2010) for providing financial support.
and subsequent cyclization gave a very good yield of benzoxazi-
nyl oxazolidinone 13a (Scheme 3). To get other substituted
oxazolidinone compounds, acid 4a was converted to Weinreb
Experimental
amide 14a, which could be a versatile building block. However,
General
to our surprise, it did not undergo any reaction with a
All reactions were conducted using oven-dried glassware under
an atmosphere of argon (Ar) or nitrogen (N2). Commercial
grade reagents were used without further purification. Solvents
were dried and distilled following usual protocols. Column
chromatography was carried out using silica gel
(100–200 mesh). TLC was performed on aluminium-backed
plates coated with Silica gel 60 with F254 indicator. The 1H
NMR spectra were recorded at 400 MHz and 13C NMR spectra
were recorded at 100 MHz using CDCl3 and DMSO-d6. 1H NMR
chemical shifts are expressed in parts per million (δ) relative to
CDCl3 (δ = 7.26) and DMSO-d6 (δ = 2.49); 13C NMR chemical
shifts are expressed in parts per million (δ) relative to the
CDCl3 resonance (δ = 77.0) and DMSO-d6 (δ = 39.7). High
resolution mass spectra (HRMS) were measured with a QTOF I
(quadrupole–hexapole TOF) mass spectrometer with an
orthogonal Z-spray–electro-spray interface. Sulfamidates 6 and
9 were prepared by following the literature procedure.11
Grignard reagent under different conditions; in some cases
ring-opening product 16a was obtained as a minor side
product. It was presumed that the bulky tert-butyl group in the
less flexible benzoxazine moiety might be inhibiting the
approach of the Grignard reagent. Also to note is that the syn-
thesis of the Weinreb amide led to 10–15% epimerization.
Amide coupling with other amines also shows similar findings
(not shown in the scheme). Boc-deprotection of the Weinreb
amide 14a with TFA gave unprotected amide 18a. To obtain
enantiopure Weinreb amide 18a, the reaction sequence was
reversed and this was successful in obtaining amide 18a
without any loss of ee. Weinreb amide 18a was treated with
PhMgBr at 0 °C and gave desired amino ketone 19a. Without
any purification, it was reduced with NaBH4 at 0 °C and
afforded amino alcohol 20a as a diastereomeric mixture (dr
4 : 1) in good yield with preservation of enantiopurity.
The amino alcohol 20a was treated with triphosgene and Et3N
and gave benzoxazinyl oxazolidinone 21a in 80% yield.
Hydride transfer was expected to be from the less hindered
side via a chelated transition state and led to the anti-
General procedure for the synthesis of
N-Boc-β-(2-bromoaryloxy)-amino acid 3
product as the major diastereomer. The cis-stereochemistry To a suspended solution of NaH (60% in oil; 0.105 g,
of benzoxazinyl oxazolidinone 21a (major isomer) was 2.6 mmol) in THF (3.0 mL), 2-bromophenol (0.152 g,
assigned from the coupling constant of the benzylic proton 0.88 mmol) was added at 0 °C. The reaction mixture was
[Jcis = 9.0 Hz (major isomer) and Jtrans = 7.6 Hz (minor isomer)] stirred for 10 min and then it was brought to 0 °C. Serine sul-
and by NOE experiment. Thus the reaction of different nucleo- famidate acid 6 (0.224 g, 0.84 mmol) in dry THF (1.0 mL) was
philes with the Weinreb amide 18 can lead to a wide variety slowly added to it at 0 °C. After 6 h, the reaction mixture was
of benzoxazinyl oxazolidinones by following this reaction acidified (pH 2; monitored by pH paper) by addition of
sequence.
NaHSO4. It was then extracted with ethyl acetate (3 × 20 mL),
the combined organic layers were washed with brine (100 mL),
dried over sodium sulfate and purified by column chromato-
graphy to get the β-(2-bromophenoxy)-α-amino acid 3a (0.17 g,
56%).
Conclusion
In summary, we have developed an efficient and general proto-
(S)-3-(2-Bromophenoxy)-2-((tert-butoxycarbonyl)amino)-pro-
1
col for the enantiopure synthesis of N-Boc-dihydrobenzo-1,4- panoic acid (3a). Yield 56%; light yellow semi-solid, H NMR
oxazine-3-carboxylic acids from β-(2-bromoaryloxy)amino acids (400 MHz, DMSO-d6): 12.95 (br s, 1H), 7.56 (d, J = 7.8 Hz, 1H),
via intramolecular aminoarylation. RuPhos Palladacycle along 7.33 (t, J = 8.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 8.2
with additional RuPhos ligand was found to be an efficient Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H), 4.41–4.38 (m, 1H), 4.32–4.29
catalyst for the aminoarylation. The method is generalized (m, 1H), 4.25–4.20 (m, 1H), 1.39 (s, 9H). 13C NMR (100 MHz,
with a variety of substrates and provides easy and direct DMSO-d6): 171.1, 155.2, 154.3, 132.9, 128.9, 122.4, 114.0,
access to N-Boc dihydrobenzo-1,4-oxazine-3-carboxylic acids in 111.1, 78.3, 68.3, 53.1, 28.1(3C). LC-MS (ESI): 358.0 [M − H]−.
moderate to very good yields with complete preservation of HRMS (ESI): calcd for C14H18BrNNaO5 382.0266 m/z [M + Na]+,
enantiopurity. Benzoxazine-3-carboxylic acid is not only the found 382.0266. HPLC analysis: Chiralpak IA (4.6 × 250 mm)
fundamental moiety of potential drugs but could be a key pre- 5μ, (MeOH) 1.0 mL min−1, 275 nm, tr (major) 7.73, tr (minor)
cursor for the synthesis of important bioactive compounds. 6.63, ee > 99%, [α]2D5 = +33.4 (c 0.52, MeOH). HPLC for the
This is exemplified with the synthesis of benzoxazinyl oxazoli- D-isomer: HPLC analysis: Chiralpak IA (4.6 × 250 mm) 5μ,
dinones from a benzoxazine carboxylic acid-derived Weinreb (MeOH) 1.0 mL min−1, 275 nm, tr (major) 6.66, tr (minor)
amide. The developed protocol is a general approach for the 7.77, ee > 99%, [α]2D5 = −33.2 (c 0.52, MeOH).
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(S)-3-(2-Bromo-4-methylphenoxy)-2-((tert-butoxycarbonyl)-
(S)-3-(2-Bromo-4,5-dimethoxyphenoxy)-2-((tert-butoxy-carbo-
amino)propanoic acid (3b). Yield 54%; light yellow sticky nyl)amino)propanoic acid (3g). Yield 63%; brown solid,
solid, 1H NMR (400 MHz, DMSO-d6): 7.38 (s, 1H), 7.12–7.10 m.p. 138–140 °C. 1H NMR (400 MHz, DMSO-d6): 12.9 (br s,
(m, 1H), 6.99–6.97 (m, 1H), 6.88–6.86 (m, 1H), 6.79 (d, J = 7.2 1H), 7.10 (s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.84 (s, 1H), 4.35 (m,
Hz, 1H), 4.33–4.19 (m, 3H), 2.22 (s, 3H), 1.38 (s, 9H). 13C NMR 1H), 4.25–4.19 (m, 2H), 3.78 (s, 3H), 3.71 (s, 3H), 1.39 (s, 9H).
(100 MHz, DMSO-d6): 171.1, 155.1, 152.3, 133.1, 131.6, 129.1, 13C NMR (100 MHz, DMSO-d6): 171.2, 155.2, 148.9, 148.6,
114.0, 110.9, 78.1, 68.8, 53.4, 28.1 (3C), 19.5. LC-MS (ESI): 144.1, 116.0, 101.7, 100.8, 78.3, 69.7, 56.2, 55.8, 53.3, 28.1 (3C).
374.3 [M − H]−. HRMS (ESI): calcd for C15H20BrNNaO5 HRMS (ESI): calcd for C16H22BrNNaO7 442.0477 m/z [M + Na]+,
396.0423 m/z [M + Na]+, found 396.0423; [α]2D5 = +33.9 (c 0.50, found 442.0477; [α]2D5 = + 24.0 (c 0.20, MeOH).
MeOH).
(S)-3-((6-Bromobenzo[d][1,3]dioxol-5-yl)oxy)-2-((tert-butoxy-
(S)-3-(2-Bromo-4-ethylphenoxy)-2-((tert-butoxycarbonyl)- carbonyl)amino)propanoic acid (3h). Yield 58%; brown sticky
1
amino)propanoic acid (3c). Yield 55%; colourless sticky solid, H NMR (400 MHz, DMSO-d6): 12.92 (br s, 1H), 7.16 (s,
1
liquid, H NMR (400 MHz, DMSO-d6): 12.96 (br s, 1H), 7.40 (s, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.93 (s, 1H), 6.02 (s, 2H),
1H), 7.16 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 4.38–4.35 4.34–4.31 (m, 1H), 4.23–4.20 (m, 1H), 4.18–4.13 (m, 1H), 1.39
(m, 1H), 4.28–4.25 (m, 1H), 4.21–4.17 (m, 1H), 2.56–2.50 (m, (s, 9H). 13C NMR (100 MHz, DMSO-d6): 171.1, 155.1, 149.5,
2H), 1.39 (s, 9H), 1.13 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, 147.5, 142.1, 111.8, 101.8, 101.3, 98.3, 78.3, 69.7, 53.2,
DMSO-d6): 171.1, 155.1, 152.3, 138.1, 132.0, 127.9, 114.1, 28.1(3C). LC-MS (ESI): 403.8 [M − H]−. HRMS (ESI): calcd for
110.9, 78.2, 68.5, 53.1, 28.0 (3C), 26.8, 15.6. LC-MS (ESI): 388.2 C15H18BrNNaO7 426.0164 m/z [M + Na]+, found 426.0164;
[M − H]−. HRMS (ESI): calcd for C16H22BrNNaO5 410.0579 m/z [α]2D5 = +24.0 (c 0.20, MeOH).
[M + Na]+, found 410.0579. HPLC analysis: Chiralpak IA (4.6 ×
(S)-3-((3-Bromo-[1,1′-biphenyl]-4-yl)oxy)-2-((tert-butoxy-car-
250 mm) 5μ, (MeOH) 1.0 mL min−1, 280 nm, tr (major) 6.81, tr bonyl)amino)propanoic acid (3i). Yield 57%; white solid,
(minor) 5.99, ee > 99%, [α]2D5 = +33.0 (c 0.20, MeOH). HPLC for m.p. 112–114 °C. 1H NMR (400 MHz, DMSO-d6): 12.98 (br s,
the D-isomer: HPLC analysis: Chiralpak IA (4.6 × 250 mm) 5μ, 1H), 7.85 (d, J = 1.6 Hz, 1H), 7.64–7.63 (m, 3H), 7.44 (t, J = 7.5
(MeOH) 1.0 mL min−1, 280 nm, tr (major) 6.00, tr (minor) Hz, 2H), 7.36–7.32 (m, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.09 (d, J =
6.75, ee > 99%; [α]D25 = −33.1 (c 0.52, MeOH).
8.1 Hz, 1H), 4.42–4.41 (m, 1H), 4.38–4.35 (m, 1H), 4.30–4.26
(S)-3-(2-Bromo-5-(tert-butyl)phenoxy)-2-((tert-butoxy-carbo- (m, 1H), 1.39 (s, 9H). 13C NMR (100 MHz, DMSO-d6): 171.1,
nyl)amino)propanoic acid (3d). Yield 63%; colourless sticky 155.2, 153.8, 138.2, 134.4, 130.7, 128.8 (2C), 127.2, 127.0, 126.3
1
solid, H NMR (400 MHz, DMSO-d6): 12.96 (br s, 1H), 7.45 (d, (2C), 114.3, 111.7, 78.3, 68.5, 53.1, 28.1 (3C). LC-MS (ESI): 436.2
J = 6.7 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), [M − H]−. HRMS (ESI): calcd for C20H22BrNNaO5 458.0579 m/z
6.93 (dd, J = 8.4 Hz, J = 1.9 Hz, 1H), 4.36–4.24 (m, 3H), 1.39 [M + Na]+, found 458.0579; [α]D25 = +34.0 (c 0.22, MeOH).
(s, 9H), 1.27 (s, 9H). 13C NMR (100 MHz, DMSO-d6): 171.2,
(S)-3-(2-Bromo-3,4,5-trimethylphenoxy)-2-((tert-butoxy-carbo-
155.2, 153.9, 152.1, 132.2, 119.5, 111.9, 108.2, 78.3, 68.6, 53.2, nyl)amino)propanoic acid (3j). Yield 70%; white solid, m.
1
34.6, 30.8 (3C), 28.1 (3C). LC-MS (ESI): 414.2 [M − H]−. HRMS p. 140–142 °C. H NMR (400 MHz, DMSO-d6):12.9 (s, 1H), 6.98
(ESI): calcd for C18H26BrNNaO5 438.0892 m/z [M + Na]+, found (d, J = 8.32 Hz, 1H), 6.81 (s, 1H), 4.50–4.35 (m, 1H), 4.25–4.15
438.0892; [α]2D5 = +25.0 (c 0.23, MeOH).
(m, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 2.14 (s, 3H), 1.39 (s, 9H). 13
C
(S)-3-(2-Bromo-4-methoxyphenoxy)-2-((tert-butoxycarbonyl)- NMR (100 MHz, DMSO-d6): 171.2, 155.1, 151.8, 136.3, 135.9,
1
amino)propanoic acid (3e). Yield 64%; brown sticky solid, H 128.7, 113.3, 111.8, 78.2, 68.6, 53.2, 28.1(3C), 20.3, 19.9, 15.8.
NMR (400 MHz, DMSO-d6): 7.15 (d, J = 2.8, 1H), 7.06 (d, J = 9.0 LC-MS (ESI): 400.2 [M
−
H]−. HRMS (ESI): calcd for
Hz, 1H), 6.96–6.89 (m, 2H), 4.31 (m, 1H), 4.23–4.19 (m, 1H), C17H24BrNNaO5 424.0736 m/z [M + Na]+, found 424.0736;
4.17–4.13 (m, 1H), 3.71 (s, 3H), 1.39 (s, 9H). 13C NMR [α]D25 = +36.0 (c 0.21, MeOH).
(100 MHz, DMSO-d6): 171.2, 155.2, 154.1, 148.5, 118.2, 115.6,
(S)-3-((1-Bromonaphthalen-2-yl)oxy)-2-((tert-butoxy-carbonyl)
114.0, 111.9, 78.2, 69.3, 55.6, 53.3, 28.1 (3C), LC-MS (ESI): amino)propanoic acid (3k). Yield 68%; white solid,
390.2 [M − H]−. HRMS (ESI): calcd for C15H20BrNNaO6 m.p. 106–108 °C. 1H NMR (400 MHz, DMSO-d6): 13.0 (br s,
412.0372 m/z [M + Na]+, found 412.0372; [α]2D5 = +27.7 (c 0.51, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.94 (d, J =
MeOH).
8.0 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.52–7.45 (m, 2H), 7.11 (d,
(S)-3-(2-Bromo-5-methoxyphenoxy)-2-((tert-butoxycarbonyl)- J = 7.6 Hz, 1H), 4.50–4.38 (m, 3H), 1.39 (s, 9H). 13C NMR
amino)propanoic acid (3f). Yield 62%; colourless sticky solid, (100 MHz, DMSO-d6): 171.1, 155.2, 152.6, 132.1, 129.6, 129.2,
1H NMR (400 MHz, DMSO-d6): 12.95 (br s, 1H), 7.43 (d, J = 8.7 128.2, 128.0, 125.2, 124.5, 115.7, 108.0, 78.3, 69.2, 53.3, 28.0
Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 6.52 (3C). LC-MS (ESI): 410.2 [M − H]−. HRMS (ESI): calcd for
(dd, J = 8.7 Hz, J = 2.3 Hz, 1H), 4.39–4.36 (m, 1H), 4.31–4.28 C18H20BrNNaO5 432.0423 m/z [M + Na]+, found 432.0423;
(m, 1H), 4.24–4.20 (m, 1H), 3.75 (s, 3H), 1.39 (s, 9H). 13C NMR [α]D25 = +45.0 (c 0.20, MeOH).
(100 MHz, DMSO-d6): 171.1, 159.9, 155.2, 154.9, 132.8, 127.6,
(S)-3-(2-Bromophenoxy)-2-((4-methoxybenzyl)amino)-propa-
121.6, 101.2, 78.3, 68.4, 55.4, 53.1, 28.1 (3C). LC-MS (ESI): noic acid (10a). Yield 72%; white solid, m.p. 166–168 °C. 1H
389.9 [M − H]−. HRMS (ESI): calcd for C15H20BrNNaO6 NMR (400 MHz, DMSO-d6): 7.60 (d, J = 7.8 Hz, 1H), 7.41 (d, J =
412.0372 m/z [M + Na]+, found 412.0372; [α]2D5 = +33.0 (c 0.23, 8.44 Hz, 2H), 7.36 (t, J = 8.24 Hz, 1H), 7.15 (d, J = 8.12 Hz, 1H),
MeOH).
6.96–6.92 (m, 3H), 4.49–4.46 (m, 1H), 4.40–4.35 (m, 1H), 4.17
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(s, 2H), 3.87 (m, 1H), 3.75 (s, 3H). 13C NMR (100 MHz, DMSO- m/z [M + Na]+, found 330.1317, HPLC analysis: Chiralpak IA
d6):167.8, 159.4, 154.1, 133.1, 131.2 (2C), 129.2, 125.4, 122.8, (4.6 × 250 mm) 5μ, (MeOH) 1.0 mL min−1, 240 nm, tr (major)
114.1, 114.0 (2C), 111.1, 68.3, 58.5, 55.2, 49.6. LC-MS (ESI): 5.08, tr (minor) 4.59, ee > 99%, [α]2D5 = −72.0 (c 0.20, MeOH).
382.1 [M − H]−. HRMS (ESI): calcd for C17H18BrNNaO4 HPLC for the D-isomer: HPLC analysis: Chiralpak IA (4.6 ×
402.0317 m/z [M + Na]+, found 402.0317; [α]2D5 = +8.0 (c 0.17, 250 mm) 5μ, (MeOH) 1.0 mL min−1, 240 nm, tr (major) 4.59, tr
MeOH).
(minor) 5.08, ee > 99%; [α]2D5 = +71.7 (c 0.20, MeOH).
(S)-4-(tert-Butoxycarbonyl)-7-isobutyl-3,4-dihydro-2H-benzo-
[b][1,4]oxazine-3-carboxylic acid (4d). Yield 72%; off-white
solid, m.p. 118–120 °C. 1H NMR (400 MHz, DMSO-d6): 8.07 (br
General procedure for intramolecular arylamination
(Buchwald–Hartwig coupling)
To compound 3a (0.1 g, 0.28 mmol) in dioxane (5 ml) was s, 1H), 6.89 (dd, J = 8.8 Hz, J = 1.6 Hz, 1H), 6.77 (d, J = 1.6 Hz,
added RuPhos Palladacycle (0.01 g, 0.014 mmol), RuPhos 1H), 4.89 (m, 1H), 4.58 (d, J = 10.9 Hz, 1H), 4.02 (dd, J = 11.1
(0.085 g, 0.014 mmol) and Cs2CO3 (0.217 g, 0.67 mmol). The Hz, J = 2.5 Hz, 1H), 1.46 (s, 9H), 1.22 (s, 9H). 13C NMR
reaction mixture was degassed with argon for 15 min, and (100 MHz, DMSO-d6): 170.5, 151.7, 145.3, 144.6, 123.9, 120.6,
then heated at 100 °C in a preheated oil bath for 15 h. Dioxane 117.4, 113.3, 80.7, 65.7, 55.8, 33.6, 30.9 (3C), 27.7 (3C). LC-MS
was then evaporated under reduced pressure. To the crude (ESI): 334.3 [M − H]−. HRMS (ESI): calcd for C18H25NNaO5
mass, water (10 ml) was added and the mixture was extracted 358.1630 m/z [M + Na]+, found 358.1634; [α]D25 = −50 (c 0.21,
with ethyl acetate (3 × 10 ml). The aqueous portion was acidi- MeOH).
fied with aqueous NaHSO4 to maintain pH 3–4 and then
(S)-4-(tert-Butoxycarbonyl)-6-methoxy-3,4-dihydro-2H-benzo-
extracted with ethylacetate (3 × 10 ml); the organic layer [b][1,4]oxazine-3-carboxylic acid (4e). Yield 78%; light yellow
was then washed with brine, dried over sodium sulphate solid, m.p. 110–112 °C. 1H NMR (400 MHz, DMSO-d6): 13.15
and the solvent was evaporated to obtain the product 4a (br s, 1H), 7.85 (br s, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.53 (dd, J =
which was purified by column chromatography. Yield: 0.059 g 8.8 Hz, J = 2.6 Hz, 1H), 5.00 (m, 1H), 4.53 (d, J = 11.3 Hz, 1H),
(76%).
4.05 (dd, J = 11.5 Hz, J = 2.7 Hz, 1H), 3.69 (s, 3H), 1.48 (s, 9H).
(S)-4-(tert-Butoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]- 13C NMR (100 MHz, MeOD): 172.7, 155.5, 153.9, 141.3, 128.1,
oxazine-3-carboxylic acid (4a). Yield 76%; light brown sticky 118.4, 110.5, 108.3, 83.6, 66.9, 57.8, 56.3, 28.6 (3C). LC-MS
1
solid, H NMR (400 MHz, DMSO-d6): 13.16 (br s, 1H), 8.15 (br (ESI): 307.8 [M − H]−. HRMS (ESI): calcd for C15H19NNaO6
s, 1H), 6.92–6.85 (m, 3H), 5.06 (m, 1H), 4.58 (d, J = 11.6 Hz, 332.1110 m/z [M + Na]+, found 332.1110; [α]D25 = −59.7 (c 0.52,
1H), 4.13 (d, J = 11.1 Hz, 1H), 1.47 (s, 9H). 13C NMR (100 MHz, MeOH).
DMSO-d6): 170.3, 151.6, 145.0, 126.2, 122.9, 121.3, 120.9,
(S)-4-(tert-Butoxycarbonyl)-7-methoxy-3,4-dihydro-2H-benzo-
116.7, 81.5, 65.4, 55.3, 27.6 (3C). LC-MS (ESI): 278.2 [M − H]−. [b][1,4]oxazine-3-carboxylic acid (4f). Yield 77%; grey solid,
HRMS (ESI): calcd for C14H17NNaO5 302.1004 m/z [M + Na]+, m.p. 120–122 °C. 1H NMR (400 MHz, DMSO-d6): 13.12 (br s,
found 302.1004; HPLC analysis: Chiralpak IA (4.6 × 250 mm) 1H), 8.12 (br s, 1H), 6.50 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 6.42 (d,
5μ, (MeOH) 1.0 mL min−1, 240 nm, tr (major) 5.88, tr (minor) J = 2.4 Hz, 1H), 5.05 (m, 1H), 4.59 (d, J = 11.2 Hz, 1H), 4.12 (dd,
5.45, ee > 99%, [α]D25 = −40.8 (c 0.49, MeOH). HPLC for the J = 11.3 Hz, J = 2.7 Hz, 1H), 3.68 (s, 3H), 1.46 (s, 9H). 13C NMR
D-isomer: HPLC analysis: Chiralpak IA (4.6 × 250 mm) 5μ, (100 MHz, DMSO-d6): 170.3, 155.0, 151.5, 145.7, 121.9, 119.3,
(MeOH) 1.0 mL min−1, 240 nm, tr (major) 5.49, tr (minor) 106.9, 101.8, 81.1, 65.7, 55.1, 54.9, 28.1 (3C). LC-MS (ESI): 308.2
5.88, ee > 99%; [α]2D5 = +40.6 (c 0.50, MeOH). [M − H]−. HRMS (ESI): calcd for C15H19NNaO6 332.1110 m/z
(S)-4-(tert-Butoxycarbonyl)-6-methyl-3,4-dihydro-2H-benzo- [M + Na]+, found 332.1110; [α]D25 = −51 (c 0.23, MeOH).
[b][1,4]oxazine-3-carboxylic acid (4b). Yield 74%; off-white (S)-4-(tert-Butoxycarbonyl)-6,7-dimethoxy-3,4-dihydro-2H-
solid, m.p. 132–134 °C. 1H NMR (400 MHz, DMSO-d6): 13.13 benzo[b][1,4]oxazine-3-carboxylic acid (4g). Yield 80%; light
(br s, 1H), 8.02 (br s, 1H), 6.72–6.70 (m, 2H), 5.02 (m, 1H), 4.55 yellow solid, m.p. 148–150 °C. 1H NMR (400 MHz, MeOD): 7.94
(d, J = 11.2, 1H), 4.08 (dd, J = 11.6 Hz, J = 2.8 Hz, 1H), 2.22 (s, (br s, 1H), 6.48 (s, 1H), 5.07 (m, 1H), 4.65 (d, J = 10.4, 1H), 4.08
3H), 1.47 (s, 9H). 13C NMR (100 MHz, DMSO-d6): 170.3, 151.5, (dd, J = 11.2 Hz, J = 2.9 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 1.53
142.8, 129.7, 125.8, 123.4, 121.2, 116.4, 81.3, 65.3, 55.3, 27.6 (s, 9H). 13C NMR (100 MHz, DMSO-d6): 170.3, 151.7, 144.7,
(3C), 20.6. LC-MS (ESI): 292.4 [M − H]−. HRMS (ESI): calcd for 142.3, 138.8, 118.2, 106.4, 101.5, 81.3, 65.6, 56.0, 55.6, 54.9,
C15H19NNaO5 316.1161 m/z [M + Na]+, found 316.1161; [α]2D5
−56.0 (c 0.20, MeOH).
=
27.7 (3C). LC-MS (ESI): 338.0 [M − H]−. HRMS (ESI): calcd for
C16H21NNaO7 362.1216 m/z [M + Na]+, found 362.1216; [α]2D5
=
(S)-4-(tert-Butoxycarbonyl)-6-ethyl-3,4-dihydro-2H-benzo[b] −61.0 (c 0.22, MeOH).
[1,4]oxazine-3-carboxylic acid (4c). Yield 73%; grey solid, (S)-8-(tert-Butoxycarbonyl)-7,8-dihydro-6H-[1,3]dioxolo-
m.p. 112–114 °C. 1H NMR (400 MHz, DMSO-d6): 13.13 (br s, [4′,5′:4,5]benzo[1,2-b][1,4]oxazine-7-carboxylic acid (4h). Yield
1H), 8.02 (br s, 1H), 6.78–6.73 (m, 2H), 5.04 (m, 1H), 4.55 (d, J = 78%; brown sticky solid; 1H NMR (400 MHz, DMSO-d6): 7.69
11.3 Hz, 1H), 4.08 (dd, J = 11.3 Hz, J = 2.9 Hz, 1H), 2.55–2.50 (br s, 1H), 6.43 (s, 1H), 5.89 (d, J = 8.0 Hz, 2H), 4.74 (m, 1H),
(m, 2H), 1.48 (s, 9H), 1.15 (t, J = 7.6 Hz, 3H). 13C NMR 4.56 (d, J = 10.3 Hz, 1H), 3.94 (dd, J = 10.5 Hz, J = 2.7 Hz, 1H),
(100 MHz, DMSO-d6): 170.4, 151.6, 143.0, 136.2, 125.8, 122.3, 1.44 (s, 9H). 13C NMR (100 MHz, DMSO-d6): 170.2, 151.5,
120.3, 116.4, 81.4, 65.3, 55.2, 27.8, 27.7 (3C), 15.8. LC-MS (ESI): 142.4, 140.9, 139.8, 118.9, 101.9, 100.8, 98.2, 81.3, 65.7, 55.0,
306.0 [M − H]−. HRMS (ESI): calcd for C16H21NNaO5 330.1317 27.6 (3C). LC-MS (ESI): 322.0, [M − H]−. HRMS (ESI): calcd for
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C15H17NNaO7 346.0903 m/z [M + Na]+, found 346.0903; [α]2D5
−65.0 (c 0.15, MeOH).
=
by column chromatography. Yield: 0.048 g (83%); off white
solid, m.p. 132–134 °C; H NMR (400 MHz, CDCl3): 7.98 (dd,
1
(S)-4-(tert-Butoxycarbonyl)-6-phenyl-3,4-dihydro-2H-benzo[b]- J = 7.7 Hz, J = 1.2 Hz, 1H), 7.06–7.01 (m, 2H), 6.99–6.93 (m,
[1,4]oxazine-3-carboxylic acid (4i). Yield 72%; light yellow 1H), 4.63 (t, J = 8.8 Hz, 1H), 4.47 (dd, J = 10.6 Hz, J = 3.1 Hz,
solid, m.p. 130–132 °C. 1H NMR (400 MHz, DMSO-d6): 8.49 (br 1H), 4.31–4.23 (m, 1H), 4.11–4.07 (m, 1H), 3.88 (t, J = 10.3 Hz,
s, 1H), 7.56–7.55 (m, 2H), 7.44 (t, J = 7.3 Hz, 2H), 7.34–7.30 (m, 1H). 13C NMR (100 MHz, CDCl3): 154.2, 144.3, 124.8, 123.1,
1H), 7.19 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.01 (m, 121.8, 119.6, 116.9, 66.7, 63.5, 50.5. LC-MS (ESI): 192.0 [M +
1H), 4.65 (d, J = 10.8, 1H), 4.12 (d, J = 10.6 Hz, 1H), 1.49 (s, H]+. HRMS (ESI): calcd for C10H9NO3, 192.0661 m/z [M + H]+,
9H). 13C NMR (100 MHz, DMSO-d6): 170.3, 151.8, 144.8, 140.3, found 192.0655; [α]D25 = −51 (c 0.26, CHCl3).
132.9, 128.8 (2C), 126.7, 126.1 (2C), 121.1, 119.3, 117.1 (2C),
(S)-tert-Butyl-3-(methoxy(methyl)carbamoyl)-2H-benzo[b]-
81.2, 65.8, 55.8, 27.7 (3C). LC-MS (ESI): 354.4 [M − H]−. HRMS [1,4]oxazine-4(3H)-carboxylate (14a). To the acid 4a (0.050 g,
(ESI): calcd for C20H21NNaO5 378.1317 m/z [M + Na]+, found 0.18 mmol) in dry THF (2 ml) was added EDC·HCl (0.052 g,
378.1317; [α]2D5 = −113 (c 0.21, MeOH).
0.26 mmol), HOBT (0.036 g, 0.26 mmol), diisopropylethyl-
(S)-1-(tert-Butoxycarbonyl)-2,3-dihydro-1H-naphtho[2,1-b]- amine (0.1 ml, 0.55 mmol) and hydrochloride salt of Weinreb
[1,4]oxazine-2-carboxylic acid (4k). Yield 55%; off-white sticky amine (0.021 g, 0.21 mmol) successively. The reaction mixture
solid, 1H NMR (400 MHz, MeOD): 7.81 (d, J = 8.4 Hz, 1H), 7.72 was stirred at rt overnight. THF was evaporated under reduced
(d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.43 (t, J = 8.0 Hz, pressure and water (5 ml) was added to the crude mixture,
1H), 7.30 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 5.45 (m, which was extracted with ethyl acetate (3 × 5 ml). The organic
1H), 4.93 (d, J = 11.2 Hz, 1H), 4.33 (dd, J = 10.9 Hz, J = 4.0, 1H), layer was washed with brine, dried over sodium sulphate, evap-
1.36 (s, 9H). 13C NMR (100 MHz, DMSO-d6): 169.4, 152.9, orated and purified by column chromatography to obtain
144.3, 129.6, 128.5, 127.4, 126.5, 125.0, 123.6, 123.2, 118.0, the desired product. Yield: 0.045 g (77%); off white solid,
1
117.6, 81.2, 67.0, 53.9, 27.5 (3C). LC-MS (ESI): 328.2, [M − H ]−. m.p. 118–120 °C, H NMR (400 MHz, DMSO-d6): 8.20 (bs, 1H),
HRMS (ESI): calcd for C18H19NNaO5 352.1161 m/z [M + Na]+, 6.91–6.88 (m, 2H), 6.82–6.79 (m, 1H), 5.29 (m, 1H), 4.47 (dd,
found 352.1160; [α]2D5 = +7 (c 0.10, MeOH).
J = 11.7 Hz, J = 1.68 Hz, 1H), 4.19 (dd, J = 11.7 Hz, J = 3.44 Hz,
3-(hydroxymethyl)-2H-benzo[b][1,4]oxazine- 1H), 3.77 (s, 3H), 3.14 (s, 3H), 1.46 (s, 9H). 13C NMR (100 MHz,
(R)-tert-Butyl
4(3H)-carboxylate (12a). To the acid compound (4a) (0.6 g, DMSO-d6): 168.3, 151.5, 145.5, 127.4, 122.5, 121.1, 120.6,
2.1 mmol) in dry THF (13 ml) was added diisopropyl amine 116.6, 81.5, 64.7, 61.2, 54.4, 32.0, 27.7 (3C). LC-MS (ESI): 323.1
(0.94 ml, 5.4 mmol). Ethylchloroformate (0.23 ml, 2.3 mmol) [M
was added at 0 °C and the mixture was stirred at 0 °C for C16H22N2NaO5 345.1426 m/z [M + Na]+, found 345.1426.
20 min. NaBH4 (0.327 g, 8.6 mmol) was added followed by (S)-3,4-Dihydro-2H-benzo[b][1,4]oxazine-3-carboxylic
+ +
H]+, 340.1 [M NH4]+, HRMS (ESI): calcd for
acid
MeOH (2.2 ml) at 0 °C. The reaction mixture stirred at rt for (18a). To the acid 4a (0.1 g, 0.36 mmol) in DCM (4 ml) was
1 h. THF and MeOH were evaporated under reduced pressure. added TFA (0.3 ml, 3.6 mmol) at 0 °C. The reaction mixture
To the crude mass, water (15 ml) was added and the solution was stirred at 0 °C for 1 h. DCM and TFA were then evaporated
was then extracted with ethylacetate (3 × 15 ml), dried over under reduced pressure. To the crude Boc-deprotected acid in
sodium sulphate, evaporated and purified by column chrom- dry THF (4 ml) was added EDC·HCl (0.104 g, 0.54 mmol),
atography to obtain the desired product. Yield: 0.37 g, (65%); HOBT (0.073 g, 0.54 mmol), diiosopropylethylamine (0.23 ml,
yellow sticky liquid, 1H NMR (400 MHz, CDCl3): 7.83 (d, J = 1.3 mmol) and Weinreb amine (0.043 g, 0.44 mmol). The reac-
8.04 Hz, 1H), 6.97–6.93 (m, 1H), 6.89–6.84 (m, 2H), 4.64–4.61 tion mixture was stirred at rt overnight. THF was evaporated
(m, 1H), 4.44 (d, J = 11.2 Hz, 1H), 4.09 (dd, J = 11.2 Hz, J = 2.7 under reduced pressure and water (6 ml) was added to the
Hz, 1H), 3.67–3.63 (m, 2H), 1.76 (t, J = 5.8 Hz, 1H), 1.55 (s, 9H). reaction mixture, which was then extracted with ethyl acetate
13C NMR (100 MHz, CDCl3): 152.8, 144.9, 124.3, 124.1, 123.4, (3 × 6 ml). The organic layer was washed with brine, dried over
120.7, 116.9, 82.1, 64.4, 59.9, 51.9, 28.3 (3C). LC-MS (ESI): sodium sulphate and purified by column chromatography.
266.3 [M + H]+. HRMS (ESI): calcd for C14H19NNaO4, 288.1212 Yield: 0.043 g (54%); yellowish liquid, 1H NMR (400 MHz,
m/z [M + Na]+, found 288.1212. HPLC analysis: Chiralpak AD-H DMSO-d6): 6.70–6.65 (m, 2H), 6.62–6.60 (m, 1H), 6.48–6.44 (m,
(4.6 × 250 mm) 5μ, (EtOH) 0.5 mL min−1, 242 nm, tr (major) 1H), 5.87 (s, 1H), 4.37–4.36 (m, 1H), 4.22 (dd, J = 10.8 Hz, J =
6.78, tr (minor) 7.28; >98% ee; [α]2D5 = −27 (c 0.2, MeOH). From 2.9 Hz, 1H), 4.10 (dd, J = 10.6 Hz, J = 4.1 Hz, 1H), 3.73 (s, 3H),
D-serine: yellow sticky liquid, HPLC analysis: Chiralpak AD-H 3.14 (s, 3H). 13C NMR (100 MHz, CDCl3): 169.5, 143.7, 131.9,
(4.6 × 250 mm) 5μ, (EtOH), 0.5 mL min−1, 242 nm, tr (major) 121.9, 119.3, 117.5, 116.7, 64.8, 61.6, 51.8, 32.5. LC-MS (ESI):
7.26, tr (minor) 6.78, >99% ee, [α]2D5 = +26 (c 0.22, MeOH).
223.2 [M + H]+, 245.1 [M + Na]+, HPLC analysis: Cellulose-1
(S)-3a,4-Dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (4.6 × 250 mm) 5μ, (MeOH) Containing 75% CO2, 2 mL min−1
,
(13a). To the alcohol 12a (0.081 g, 0.3 mmol) in DMF (1 ml) 210 nm, tr (major) 3.75, tr (minor) 4.35; >99% ee; [α]2D5 = −33.4
was slowly added aqueous (6 N) NaOH solution (0.07 ml) at (c 0.5, DCM). HRMS (ESI): calcd for C11H14N2NaO3, 245.0902
0 °C. The reaction mixture was stirred at 0 °C for 1 h. Water m/z [M + Na]+, found 245.0902. From D-serine: yellowish liquid,
(5 ml) was added to the reaction mixture, which was then HPLC analysis: Cellulose-1 (4.6 × 250 mm) 5μ, (MeOH) con-
extracted with ethyl acetate (3 × 5 ml). The organic layer was taining 75% CO2, 2 mL min−1, 210 nm, tr (major) 4.35, tr
washed with brine, dried over sodium sulphate and purified (minor) 3.76; >99% ee; [α]2D5 = +33.5 (c 0.5, DCM).
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(R)-((S)-3,4-Dihydro-2H-benzo[b][1,4]oxazin-3-yl)(phenyl)-
methanol (20a). To the Boc-deprotected Weinreb amide 18a
(0.167 g, 0.75 mmol) in dry THF (2 ml) was added phenylmag-
nesium bromide (1 M, in THF, 2 ml) at 0 °C. The reaction
mixture was stirred at 0 °C for 30 min. The reaction mixture
was then quenched with saturated NH4Cl (4 ml) and extracted
with ether (3 × 6 ml). The organic layer was dried over sodium
sulphate and evaporated under reduced pressure at room
temperature. The crude compound was immediately used for
the next step without further purification.
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To the crude compound 19a (0.180 g, 0.75 mmol) in MeOH
(4 ml) was added NaBH4 (0.029 g, 0.75 mmol) at 0 °C. The
reaction mixture was stirred at 0 °C for 30 min. MeOH was
then evaporated under reduced pressure. To the crude product
was added NH4Cl (5 ml) and the mixture was then extracted
with ethyl acetate (3 × 6 ml). The organic layer was washed
with brine, dried over sodium sulphate, evaporated under
reduced pressure, and purified by column chromatography
to afford the desired product 20a. Yield: 0.128 g (70%);
sticky liquid, 1H NMR (400 MHz, CDCl3): 7.42–7.35 (m, 5H),
6.81–6.78 (m, 1H), 6.75–6.63 (m, 2H), 6.46 (d, J = 7.2 Hz, 1H),
4.71–4.67 (m, 1H), 4.33 (d, J = 4.1 Hz, 2H), 3.57–3.45 (m, 1H),
3.39 (bs, 1H), 2.21 (bs, 1H). 13C NMR (100 MHz, CDCl3): major
isomer: 143.6, 140.3, 132.3, 128.5 (2C), 128.2, 126.4 (2C),
121.2, 118.5, 116.2, 115, 73.2, 65.5, 54.4. LC-MS (ESI): 242.2
[M + H]+. HRMS (ESI): calcd for C15H15NNaO2, 264.1000 m/z
[M + Na]+, found 264.1000. HPLC analysis: YMC Amylose-C
(4.6 × 250 mm) 5μ, (EtOH) 0.5 mL min−1, 220 nm, major dia-
stereomer tr (major) 16.68, tr (minor) 10.16, ee > 99%, minor
diastereomer, tr (major) 13.66, tr (minor) 14.86; ee > 99%.
(3R,3aS)-3-Phenyl-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]-
oxazin-1(3H)-one (21a). To the amino alcohol 20a (0.062 g,
0.26 mmol) in dry DCM (4 ml) was added Et3N (0.09 ml,
0.64 mmol) and then triphosgene (0.08 g, 0.27 mmol) at 0 °C.
The reaction mixture was stirred at 0 °C for 20 min. Water
(6 ml) was added to the reaction mixture, which was then
extracted with DCM (3 × 8 ml). The organic layer was washed
with brine, dried over sodium sulphate, evaporated and puri-
fied by column chromatography to obtain the desired product.
Yield: 0.055 g (80%); white solid, m.p. 122–124 °C; 1H NMR
(400 MHz, CDCl3): major isomer of 21a 8.08–8.05 (m, 1H),
7.48–7.38 (m, 4H), 7.30 (d, J = 6.3 Hz, 2H), 7.02–6.99 (m, 2H),
6.89–6.87 (m, 1H), 5.86 (d, J = 9.0, 1H), 4.41 (dt, J = 10.4 Hz, J =
2.8 Hz, 1H), 3.87 (dd, J = 11.0 Hz, J = 2.8 Hz, 1H), 3.24 (t, J =
10.7 Hz, 1H), 13C NMR (100 MHz, CDCl3): major isomer:
153.7, 143.8, 133.4, 129.2, 128.6 (2C), 124.9 (2C), 124.5, 123.2,
121.4, 119.4, 116.5, 75.1, 64.7, 53.4. LC-MS (ESI): 268.0
[M + H]+. HRMS (ESI): calcd for C16H13NNaO3, 290.0793 m/z 10 (a) Q. Xin, H. Fan, B. Guo, H. He, G. Suo, H. Wang,
[M + Na]+, found 290.0793.
Y. Huang and Y. Yang, J. Med. Chem., 2011, 54, 7493;
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X. Chen and Y. Yang, J. Med. Chem., 2013, 56, 2642;
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Notes and references
1 Review: (a) J. Ilas, P. S. Anderluh, M. S. Dolenc and
D. Kikelji, Tetrahedron, 2005, 61, 7325; (b) P. Lestage, 11 R. Malhotra, T. K. Dey, S. Basu and S. Hajra, Org. Biomol.
B. Lockhart, M. B. Fleury and M. Largeron, WO Patent Appl,
Chem., 2014, 12, 6507.
This journal is © The Royal Society of Chemistry 2015
Org. Biomol. Chem.