Straightforward synthesis of 4,5-bifunctionalized 1,2-oxazinanes via Lewis acid promoted regio- and stereo-selective nucleophilic ring-opening of 3,6-dihydro-1,2-oxazine oxides

Article abstract of DOI:10.1016/j.tet.2019.05.015

Functionalized 1,2-oxazinanes are interesting and valuable heterocycles with potential applications in synthetic and medicinal chemistry. A straightforward strategy for quick access to unprecedented trans-4-hydroxyl-5-azido/cyano/amino 1,2-oxazinanes are developed: N-COR 3,6-dihydro- 1,2-oxazine oxides are prepared with ease from related dihydro- 1,2-oxazines and opened by nucleophiles TMSN₃, TMSCN and aryl/alkyl amines. Appropriate Lewis acid catalysts are found playing a vital role for both reaction rate and regioselectivity. The N-COR group can be removed under mild conditions to provide highly desirable NH 1,2-oxazinanes inaccessible via previous methods.

Full text of DOI:10.1016/j.tet.2019.05.015

Accepted Manuscript
Straightforward synthesis of 4,5-bifunctionalized 1,2-oxazinanes via Lewis acid
promoted regio- and stereo-selective nucleophilic ring-opening of 3,6-dihydro-1,2-
oxazine oxides
Xiu-Rong Huang, Yu-Mei Zhang, Ting-Biao Wan, Piao Zhang, Xiu-Xiu Zhang, Fang-
Ming Wang, Defeng Xu, Mei-Hua Shen, Hua-Dong Xu
PII:
S0040-4020(19)30534-4
https://doi.org/10.1016/j.tet.2019.05.015
TET 30336
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 March 2019
Revised Date: 25 April 2019
Accepted Date: 8 May 2019
Please cite this article as: Huang X-R, Zhang Y-M, Wan T-B, Zhang P, Zhang X-X, Wang F-M, Xu D,
Shen M-H, Xu H-D, Straightforward synthesis of 4,5-bifunctionalized 1,2-oxazinanes via Lewis acid
promoted regio- and stereo-selective nucleophilic ring-opening of 3,6-dihydro-1,2-oxazine oxides,
Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.05.015.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Straightforward synthesis of 4,5-
Leave this area blank for abstract info.
bifunctionalized 1,2-oxazinanes via Lewis
acid promoted regio- and stereo-selective
nucleophilic ring-opening of 3,6-dihydro-1,2-
oxazine oxides
a
a
a
a
a
b
Xiu-Rong Huang , Yu-Mei Zhang , Ting-Biao Wan , Piao Zhang , Xiu-Xiu Zhang , Fang-Ming Wang , Defeng
a
a,*
a,∗
Xu , Mei-Hua Shen and Hua-Dong Xu
a
School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu Province
13164, China.
School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology,
2
b
Zhengjiang 212003, China.
Lewis acid catalysis enabled highly selective ring-opening of 3,6-dihydro-1,2-oxazine oxide with
nucleophiles gives rise to valuable functionalized 1,2-oxazinanes with readily removable N-COR
group.

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Straightforward synthesis of 4,5-bifunctionalized 1,2-oxazinanes via Lewis acid
promoted regio- and stereo-selective nucleophilic ring-opening of 3,6-dihydro-1,2-
oxazine oxides
a
a
a
a
a
b
Xiu-Rong Huang , Yu-Mei Zhang , Ting-Biao Wan , Piao Zhang , Xiu-Xiu Zhang , Fang-Ming Wang ,
a
a,*
a,∗
Defeng Xu , Mei-Hua Shen and Hua-Dong Xu
a
School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu Province 213164, China.
School of Environmental and Chemical Engineering, Jiangsu University of Science and Technology, Zhengjiang 212003, China.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Functionalized 1,2-oxazinanes are interesting and valuable heterocycles with potential
applications in synthetic and medicinal chemistry. A straightforward strategy for quick access to
unprecedented trans-4-hydroxyl-5-azido/cyano/amino 1,2-oxazinanes are developed: N-COR
3,6-dihydro- 1,2-oxazine oxides are prepared with ease from related dihydro- 1,2-oxazines and
Available online
3
opened by nucleophiles TMSN , TMSCN and aryl/alkyl amines. Appropriate Lewis acid
catalysts are found playing a vital role for both reaction rate and regioselectivity. The N-COR
group can be removed under mild conditions to provide highly desirable NH 1,2-oxazinanes
inaccessible via previous methods.
Keywords:
1
3
,2-Oxazinane
,6-dihydro-1,2-oxazine oxide
2
009 Elsevier Ltd. All rights reserved.
Nucleophilic ring-opening of epoxide
Regioselective amination of epoxide
Regioselective azidolysis of epoxide
Regioselective cyanide addition to epoxide
1
. Introduction
,2-oxazinane or alternative tetrahydro 1,2-oxazine is a class
Doyle and co-workers developed transition metal catalyzed
formal [3+3] cycloadditions of enoldiazo compounds 6 with
nitrones to generate multiple substituted 3,6-dihydro-1,2-
ozaxines 7 which can be converted into related 1,2-oxazinanes
1
of unique six-membered heterocycles containing an endocyclic
N-O moiety which can be found in several bioactive natural
products and synthetic molecules, as exampled by FR900482,
FR66979 and their derivatives FK973, FK317 (not shown),
Phyllantidine, Alsmaphorazine A/B (Figure 1). It is also a
[15]
[16]
readily.
As pioneered by Yamamoto group,
domino
[
1]
[2]
reactions enabled by enamine catalysis also provide facile
accesses to 1,2-oxazinanes. Enantiomeric pure 1,2-oxazanes 10
were synthesized efficiently in Zhong’s laboratory through L-
[
3]
[4]
[5]
[
6]
[7]
useful intermediate in synthesis particularly for 1,4-amino
alcohols.
[17]
proline catalyzed reaction of enals 9 with nitroso arenes 8.
[
8]
Baidya and colleagues were able to convert dial 11 and nitroso
compounds 8 into optically pure oxazinanes 12 in one pot by
Recently, the synthesis of 1,2-oxazinane attracted
considerable attention and several elegant methods have been
developed. Roughly, these methods fall in two categories,
namely (formal)/[3+3] cycloadditions of nitrones 1 with a 3-
carbon synthon 2, 4 or 6 (Scheme 1a) and amine catalyzed
aldehyde α-oxyamination-cyclization casacade with nitroso
[
18]
using L-proline as enamine catalyst.
A dual-organocatalyst-
promoted asymmetric cascade devised by Sun and Lin group
realized rapid construction of densely functionalized 1,2-
oxazinanes 16 via sequential assembling of 8 with aliphatic
[
19]
aldehydes 13, enals 14, aryl amines 15. Additionally, several
other elegant yet related methods appeared in the literature
include Yu’s catalytic asymmetric intramolecular aza-Michael
[
9]
[10]
compounds (Scheme 1b). Archambeau and Rawal
disclosed conditions that promoted [3+3] cycloaddition of nitrone
with oxyallyl cations in situ generated from cyclic/acyclic α-
tosyloxy ketones 2, achieving functionalized 1,2-oxazinanes 3.
groups
[
20]
addition approach,[ Albrecht’s domino aza-Michael/Michael
1
21]
addition approach,
and Pagenkopf’s [4+2] cycloaddition of
[22]
[
11]
donor–acceptor cyclobutanes with nitrosoarenes.
Since reported by Kerr et al in 2003,
3+3] cycloaddition reaction of nitrones 1 with cyclopropanes 4
[14]
Lewis acid promoted
[
However, these methods still suffer from imperfections such
as narrow substrate scope and limited product substitution
patterns, especially removal of the unavoidable aryl or alkyl
group from Nitrogen would encounter extraordinary difficulties.
[
12]
[13]
has been advanced greatly, especially in Sibi and Tang
laboratories with respect to asymmetric catalytic version that give
rise to enantiomerically pure poly-substituted 1,2-oxazinanes 5.
—
——
∗
Corresponding author. e-mail: shenmh@cczu.edu.cn; hdxu@cczu.edu.cn.

2
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 1. Preparation of N-COR 1,2-oxazinane epoxide
Figure 1. Examples of natural and synthetic products containing 1,2-
oxazinane
a
Table 1. Conditions optimization for epoxide azidolysis
b
x
conditions
Solv
Yield (%)
entry
cat*
o
c
equiv
1.1
1.1
1.1
2.0
2.0
2.0
2.0
2.0
1.1
1.1
2.0
T ( C)
time
3 d
(α/β)
1
2
3
4
5
6
7
8
9
Cr-I
Cr-I
Cr-I
Cr-I
Cr-I
Cr-I
Cr-I
Cr-I
Co-I
Cr-II
Cr-II
DCM
40
60
40
40
40
80
80
80
40
40
40
12 (-)
THF
3 d
36 (-)
Et
2
O
O
3 d
85 (3.1/1)
94 (3.6/1)
87 (2.8/1)
98 (2.1/1)
94 (3.0/1)
70 (2.5/1)
45 (-)
Et
2
3 d
i
2
Pr O
4 d
i
2
Pr O
12 h
12 h
24 h
3 d
MTBE
DME
Scheme 2. Recent progress in 1,2-oxazinane synthesis by
using nitrone and nitrosoarene
2
Et O
2
Et O
2
Et O
1
1
0
1
3 d
80 (8.4/1)
88 (8.0/1)
3 d
Scheme 3. Proposed strategy for functionalized 1,2-
ozaxinane synthesis from 3,6-dihydro-1,2-oxazine
Therefore complementary strategy that can provide novel 1,2-
oxazinanes in efficient manner is highly demanded. We
envisioned that simple N-COR dihydro-1,2-oxazine like 17,
readily obtained from [4 + 2] cycloaddition of acyl nitroso
compound with diene, could serve as a facile starting point for
this purpose as alkene group can participate in diverse chemical
transformations. One straightforward approach is epoxidation of
a
Conditions: 18a (60.7 mg, 0.3 mmol), TMSN (1.1 or 2.0
3
o
o
equiv), cat* (15.0 ꢁmol), dry solvent (1.0 mL), 40 C - 80 C,
N , in Schlenk flask, then Bu NF (0.45 mmol). Isolated
yield. NMR ratio.
n
b
[
23]
2
4
c
With the establishment of a robust protocol for the preparation
of epoxide substrates, we set out to explore the azidolysis of the
epoxide. Initial studies showed that NaN was not a competent
reagent to open up epoxide 18a in MeOH/H O (v/v 8/1); the
TMSN /BF ꢀEt O combination in CH Cl (DCM) decomposed
1
7 followed by epoxide-opening using diverse nucleophiles to
afford 4,5-difunctionized 1,2-oxazinanes 19. Based on above
analysis, we initiated a research program at this direction and
report our preliminary results herein.
3
2
3
3
2
2
2
the oxazine oxide substrate completely to a non-productive
mixture, showing a quite different reactivity in comparison with
2
. Results and discussion
[
24]
its carbon congener cyclohexene oxide.
Finally, chromium
2
.1. Synthesis of N-COR-1,2-oxazine oxide
salen-Cr(III) complex Cr-I was identified as an effective Lewis
Our research began with the synthesis of N-COR 3,6-dihydro-
,2-oxazine oxides 18. Treatment of 3,6-dihydro-1,2-oxazine 17a
acid to promote this azidolysis with TMSN (Table 1). Although
the Cr-I (5 mol%) catalyzed reaction was very slow in DCM and
3
1
with m-CPBA afforded 18a in 56% yield. Alternatively,
bromoacetoxylation with NBS/AcOH and subsequent
deacetylation-cyclization with NaOH in MeOH can provide the
same epoxide in a higher overall yield of 78% (Scheme 3).
Several homologues 18b-d can also be made conveniently
through this two-step protocol. The bromoacetoxylation
intermediate of 17c was isolated and NMR analysis demonstrated
it was a ca. 1/1 regioisomeric mixture of two trans-1,2-
bromoacetates, indicating that the C-C double bond in 17 is
almost imperceptibly biased in stereo-electronical nature for the
bromoacetoxylation.
tetrahydrofuran (THF), it did proceed smoothly in dry ether at 40
C and completed in 3 days to give 19a in 85% yield as an α/β
3.1/1 regio isomeric mixture (Table1 entries 1, 2 vs entry 3).
19aα arises from the nucleophilic backside attack of azide anion
at C5 while 19aβ from the attack at C4. Increasing the amount of
TMSN3 from 1.1 equiv to 2.0 equiv resulted in a slightly
o
improved yield with a similar α/β ratio (entry 4: 94% yield,
i
3.6/1). Isopropyl ether ( Pr O) worked equally well as a solvent
2
(entry 5: 87% yield, α/β 2.8/1) and enhancement of the
o
temperature to 80 C accelerated this epoxide-opening process
immensely that finished up in less than 12 h giving an increased
yield albeit in conjunction with a decreased regioselectivity
2
.2. Azidolysis of the N-COR-1,2-oxazine oxide
(entry 6: 98% yield, α/β 2.1/1). Methyl tert-butyl ether (MTBE)

3
a
Table 2. The electronic effects of the N-acyl g
ACupCEPTED MANUSCRIPT
ro
Table 3. Brief optimization of aniline addition to the
a
epoxide
b
yield (%)
entry
R
time
product
o
b
c
c
entry
Cat*
-
Solv
T ( C)
Yield (%) (α/β)
(
α/β)
d
1
MTBE
MTBE
80
80
40
40
40
40
40
67 (2.0:1)
89 (3.0:1)
65 (4.1:1)
80 (5.0:1)
78 (5.7:1)
54 (9.3:1)
81 (8.0:1)
1
2
3
4
5
6
7
8
Ph
3 d
3 d
6 d
5 d
6 d
7 d
3 d
4 d
19a
19b
19c
19d
19e
19f
80 (8.4/1)
93 (1/0)
2
Cr-I
Cr-I
Cr-I
Cr-I
Cr-I
Cr-II
4-MeOPh
2-BrPh
4-ClPh
4-CNPh
d
3
MTBE
90 (6.1/1)
86 (7.7/1)
93 (6.7/1)
66 (5.0/1)
87 (8.5/1)
72 (14.2/1)
i
4
2
Pr O
d
5
2
Et O
d,e
6
DME
DME
4-NO
2
Ph
7
BnO
19g
19h
a
t
Conditions: 18a (0.3 mmol), PhNH ( 56 mg, 0.6 mmol),
Cat* (30.0 ꢁmol), dry solvent (1.0 mL), 40 C or 80 C, 3 d,
N , in Schlenk flask. Isolated yield. NMR ratio. Epoxide
detectable via TLC. 4 days instead.
BuO
2
o
o
a
Conditions: 18 (0.3 mmol), TMSN ( 38 mg, 0.33 mmol), Cr-
II (11.0 mg, 15.0 ꢁmol), dry Et O (1.0 mL), 40 C, N , in Schlenk
flask, then Bu NF (0.45 mmol). Isolated yield. NMR ratio.
b
c
d
3
o
2
e
2
2
n
b
c
4
2
.4. Amine addition to the N-acyl-1,2-oxazine oxide
showed comparable efficacy but dimethoxylethane (DME) turned
out to be inferior in regards of reaction yield and selectivity
Next, we turned our attention to the highly valuable amine
(
Entries 7 and 8). Using salen-Co(III) complex Co-I in place of
addition to 1,2-oxazinane epoxide 18 (Table 3), and quickly
disclosed that the un-catalyzed reaction of 18a with excess
aniline (2 equiv) did occur in hot MTBE (80 C) albeit slowly.
Cr-I led to a drastic decrease in catalytic effectiveness (Entry 9),
however complex Cr-II, carrying a more flexible non-cyclic
diimine as the supporting ligand, improved the regioseletivity
dramatically to α/β > 8.0/1 (entries 10 and 11).
o
After 3 days, an incomplete reaction mixture was observed from
which 21a was isolated in a form of α/β 2.0/1 inseparable
isomeric mixture in 67% yield (entry 1). Catalytic amount of Cr-
I improved the reaction rate and regioselectivity noticeably under
the same conditions (entry 2, 89% yield, α/β 3.0/1). When the
With Cr-II as the Lewis acid catalyst, the electronic effects of
the N-COR group were investigated by comparing the reaction
outcomes of 18a-h (Table 2). 18b bearing electron-releasing p-
methoxyl group delivered exclusively a single regio isomer 19bα
in 93% yield (entry 2). 18c-f with electron withdrawing groups 2-
o
i
reaction was performed at 40 C with MTBE, Pr O or Et O as
2
2
solvent, the ratio of two regioisomers increased to 4.1-5.7/1
favoring the C5 adduct 21aα (entries 3-5). With DME as solvent,
a further improvement of α/β ratio to 9.3/1 was obtained although
accompanied with a slightly decreased reaction rate (entry 6).
Finally, to our delight, the use of Cr-II as catalysis again showed
superiority that remarkably accelerated the epoxide-opening
process rendering the starting epoxide 18a completely consumed
in 3 d to give both a high yield and an excellent selectivity at the
same time (entry 7: 81% yield, α/β 8/1).
Br, 4-Cl, 4-CN and 4-NO afforded comparably high yields with
2
the exception of the moderate yield of 66% for 19f, whereas the
α/β ratio dropped into the 5.0-7.7/1 range (entries 3-6). To our
delight, epoxides 18g and 18h with the two most common amine
protecting groups were also efficiently azidolysised with
excellent regioselectivities under the catalytic effect of complex
Cr-II (entries 7 and 8).
2
.3. Cyanide addition to the N-acyl-1,2-oxazine oxide
Then, a series of substituted anilines were investigated as N-
nucleophiles for this reaction using DME as reaction medium
Cyanide addition to epoxides 18 was also intensively
(
Table 4). In most cases, the chromium salen complex Cr-II was
attempted and eventually the La(OTf) /iPr-PHOX combination
3
superior to its congener Cr-I (entries 1-7). Cr-II was able to
boost the reactions to completion in several days furnishing
higher yields and α/β ratio, in contrast, the related reactions with
Cr-I as catalyst normally proceeded much slower without full
conversion even in longer time to afford corresponding cyclic
trans vicinal amino alcohols 21a-21g in inferior yield and
selectivity. It seems that electronic donating group at the aniline
benefits the reaction rate. The reaction of 18a with p-methoxyl-
aniline catalyzed by Cr-II finished 89% yield of 21b in 3 days,
while the same reaction with para-fluoride took 6 days to
complete giving 21g in only 54% yield (entry 2 vs 7); moreover,
with stronger electron withdrawing 4-nitro-aniline, the reaction
didn’t take place at all in the presence of 10 mol% Cr-I (not
shown). The decreased reaction rate and regioselectivity (5 d,
was identified as a feasible catalysis system to realize this
transformation by using TMSCN as the cyanide source. When
carried out in the presence of 10 mol% La(OTf) and 12 mol%
3
ligand iPr-PHOX, the reaction of 18a proceeded in a slow and
selective manner to give an α/β 4.2/1 regio isomeric mixture of
trans-adduct 20a in 58% yield upon workup with TBAF.
Surprisingly, it was found that 18b is a better substrate than 18a
providing an exclusive α regioselectivity and an improved yield
of 81% in a shortened reaction time (Scheme 4), but the
underlying reasons keep elusive at present stage.
2
1cα/21cβ: 5.0/1) for o-methoxyl-aniline (OMPNH2) in
comparison with those for its para congener PMPNH might
2
reflect the steric impact of nucleophile (entry 3 vs 2).
Scheme 4. Lewis acid catalyzed epoxide-opening with
TMSCN

4
Tetrahedron
ACCEPTED MANUSCRIPT
a, b
Table 4. Epoxide opening with aryl and alkyl amines
a
o
o
Conditions: 18a, 18b or 18f (0.3 mmol), amine (0.6 mmol), Cr-I or Cr-II (30.0 ꢁmol), dry solvent (1.0 mL), 40 C or 80 C, 3
b
c
d, N , in Schleck flask. Isolated yield and NMR ratio were recorded. Epoxide detectable via TLC.
2
In line with the trend previously observed for azidolysis with
interactions between the N-substituent and the catalytic complex
TMSN (Table 2), epoxide 18f was also less reactive than 18a in
Cr-II promoted reaction with aniline and took much longer time
will define the transition-state conformation, leading to
unsymmetrical activation of the two otherwise electronically
symmetric C-O bonds and increased α/β ratio. Nevertheless,
calculations will be benefit for insightful understanding of this
catalytic reaction.
3
(10 d) to achieve a full conversion (entry 8 vs 1). Accordingly,
1
9
8b led to a significant improvement in regioselectivity to α/β:
.1/1 while a high yield of 1,2-amino alcohols 21i was remained
(
entry 9). Alkylamines such as benzylamine (BnNH ), allylamine
2
2
.5. Structure determination
(AllyNH ) and propargylamine (PgyNH ) are also feasible
2
2
nucleophiles to open up the epoxide group under the promotion
of chromium complex Cr-II, and the related adducts 21l-n were
collected with slight decline in yields and α/β ratio (entries 12-
Our attempt to determine the structures of isomeric pairs of
9α/β, 20α/β and 21α/β only by NMR analysis failed and
1
therefore our efforts were turn to crystallography. Nice
crystalline solids of 19aα and 20bα were obtained after several
careful trials of crystallization operations. To our delight,
treatment of 21iα with triphosgene and pyridine in DCM
produced solid oxazolidinone 22iα from which single crystal was
also grown with ease. X-ray diffraction experiments established
1
4). In the absence of Cr-II as catalyst, the same reaction of
o
BnNH with 18b was slow even in 80 C and delivered no regio
2
discrimination, approving that the epoxide activating effect of the
Lewis acidity tolerated stronger Lewis basicity of alkylamines as
well (entry 12). Interestingly, less nucleophilic ethyl glycinate
(
GlyNH ) reacted with 18b more efficiently giving rise to 21o in
2
a 92% combined yield with a 5.0/1 regioselectivity (entry 15). N-
heterocycles piperidine, morpholine, mono N-protected
piperazine, tetrahydroisoquinoline and pyrrolidine all underwent
this Cr-II catalyzed epoxide ring opening reaction with 18b to
provide biologically valuable alkaloids 21p-t in high to excellent
yields with good regioselectivities (entries 16-20).
In the absence of Cr-salen complex as catalyst, the dramatic
decrease or totally disappearance of regioselectivity was
observed for the amination of 18a and 18b with aniline and
benzyl amine respectively, indicating that the C4 and C5 of the
epoxide hold similar electronic properties, in line with previous
postulation based on bromoacetoxylation of 17a. One can
imagine that, upon activation of the epoxide by a Lewis acid
flanked by a big-sized ligand, the steric or/and electronic
Figure 2. X-ray structures of 19aα, 20bα and 22iα

5
the structures of the major isomers of ring
A
op
C
en
C
ingEPre
T
ac
E
tio
D
ns MA4.
N
2.
.2.1. Procedure
To a 10 mL sealed tube equipped with a stir bar were added
U
Az
S
id
C
ol
R
ys
isPT
I
1
9aα, 20bα and 21iα to be the C5-adducts as shown in Figure 2.
4
Consequently, the minor regioisomers were the corresponding
C4-adducts as shown.
Cr-II (11.0 mg, 15.0 ꢁmol), 18 (0.3 mmol), TMSN (38.0 mg,
.33 mmol) and anhydrous Et O (1.0 mL). Then the solution was
3
2
.6. Removal of the N-protecting group
0
2
evacuated and refilled with N three times and stirred for 3 - 7
days at 40 C. When completed as indicated by TLC, the reaction
mixture was concentrated in vacuo. TBAF (0.45mL, 1.0 M,
2
Removal of the 4-methoxybenzoyl N-protecting group in these
o
products would give rise to valuable small N-heterocycles ready
for further derivatization. For this purpose, 19bα and 21iα were
selected for examples and treated with NaOH in MeOH, the
hydrolysis of the amide bond proceeded smoothly in room
temperature and 4-hydoxyl-5-azido-1,2-oxazinane 23bα and 4-
hydoxyl-5-phenylamino-1,2-oxazinane 23iα were achieved
respectively in high yields (Scheme 5).
0
.45mmol) was added and the reaction mixture was stirred for 5
min. The solution was diluted with ethyl acetate (10.0 mL) and
extracted with ethyl acetate (3 x 50.0 mL). The combined organic
layers were dried over anhydrous Na SO , filtered and
2
4
concentrated under vacuum. Purification via flash column
chromatography with silica gel (eluting with PE/EA = 2/1 (v/v))
yielded 19α and 19β
4
4
.2.2. Characterization of 19
.2.2.1 19aα and 19aβ
Inseparable mixture, white waxy solid (total 59.1 mg, 80%
o
yield); m.p. 90-91 C. The area of one alkyl-H peak on the 1,2-
oxazinane ring in α isomer was compared with that in β isomer to
1
1
derive a H NMR ratio of α/β = 8.4 : 1. 19aα: H NMR (400
MHz, CDCl ) δ 7.70 – 7.64 (m, 2H), 7.49 (t, J = 7.4 Hz, 1H),
3
7
1
.41 (t, J = 7.5 Hz, 2H), 4.34 (d, J = 13.9 Hz, 1H), 4.21 – 4.13 (m,
H), 3.94 – 3.86 (m, 1H), 3.77– 3.54 (m, 3H). C NMR (101
Scheme 5. Showcases of N-aroyl deprotection
13
MHz, CDCl ) δ 170.77, 132.59, 131.61, 128.89, 128.22, 71.29,
3
. Conclusions
3
1
6
7.16, 60.28, 47.96. 19aβ: H NMR (400 MHz, CDCl ) δ 7.70 –
3
In summary, a fast entry toward valuable trans-4-hydroxyl-5-
azido/cyano/amino 1,2-oxazinanes have been developed that
features an efficient epoxidation of readily accessible N-COR
7.64 (m, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H),
4.50 (d, J = 9.52 Hz, 1H), 4.21 – 4.13 (m, 1H), 3.94 – 3.86 (m,
13
1H), 3.77 – 3.54 (m, 3H). C NMR (101 MHz, CDCl ) δ 170.77,
3
3
,6-dihydro-1,2-oxazines and a subsequent epoxide ring-opening
132.59, 131.61, 128.89, 128.22, 71.29, 67.16, 60.28, 47.96.
+
+
with nucleophiles TMSN , TMSCN and amines. Appropriate
HRMS (ESI) m/z Calculated for C H N O [M + H] 249.0982,
3
11 13 4 4
Lewis acid catalysts are critical for these regioselective
found 249.0976.
processes. For azide and cyanide addition, salen-Cr(III) complex
i
4.2.2.2 19bα
and La(OTf) / Pr-PHOX are essential for the reactions to occur
3
1
respectively. For the aminolysis of the 3,6-dihydro-1,2-oxazine
oxides with aryl and alkyl anines, salen-Cr(III) complexes as
catalysts, particularly Cr-II, improve the transformation
remarkably in two aspects: increasing the reaction rate by a large
margin that enables a much milder reaction temperature possible,
and raising the α regioselectivity to a level that renders the
method synthetically useful. The removal of the N-aroyl
protection group is achieved with efficiency to release the
corresponding free 1,2-oxazinanes, potentially useful N-
heterocycle building blocks in medicinal chemistry.
Yellow oil (α only,78.0mg, 93% yield). H NMR (400 MHz,
CDCl ) δ 7.73 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.35
3
(d, J = 12.1 Hz, 1H), 4.16 (dd, J = 11.5, 3.4 Hz, 1H), 3.94 – 3.88
1
3
(m, 1H), 3.85 (s, 3H), 3.74 – 3.55 (m, 3H). C NMR (75 MHz,
CDCl ) δ 170.70, 162.45, 131.47, 124.41, 113.47, 71.24, 67.33,
60.42, 55.53, 48.04. HRMS (ESI) m/z Calculated for
C H N O [M + H] 279.1088, found 279.1083.
3
+
+
1
2
15
4
4
4
.2.2.3 19cα and 19cβ
Inseparable mixture, yellow oil (total 88.4 mg, 90% yield).
The area of one alkyl-H peak on the 1,2-oxazinane ring in α
4
. Experimental section
1
isomer was compared with that in β isomer to derive a H NMR
1
ratio of α/β = 6.1 : 1. 19cα: H NMR (300 MHz, CDCl ) δ 7.63 –
4
.1. General information
3
7
.55 (m, 1H), 7.40 – 7.26 (m, 3H), 4.36 (d, J = 13.1 Hz, 1H),
NMR spectra were recorded using Bruker AV-300 / AV-400
4.18 – 4.05 (m, 1H), 3.98 – 3.72 (m, 2H), 3.69 – 3.48 (m, 2H).
1
3
spectrometers. The data are reported as follows: chemical shift in
ppm from internal tetramethylsilane on the δ scale, multiplicity (s
=
C NMR (75 MHz, CDCl ) δ 168.13, 136.37, 132.96, 131.02,
3
1
127.96, 127.37, 119.04, 71.60, 66.90, 60.03, 46.60. 19cβ: H
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd =
NMR (300 MHz, CDCl ) δ 7.63 – 7.55 (m, 1H), 7.40 – 7.26 (m,
3
doublet of doublets, dt = doublet of triplets, td = triplet of
doublets), coupling constants (Hz) and integration. Analytical
thin layer chromatography was performed on 0.25 mm extra hard
silica gel plates with UV254 fluorescent indicator and/or by
exposure to phosphormolybdic acid/alkalinity potassium
permanganate/ninhydrine followed by brief heating with a heat
gun. Liquid chromatography (flash chromatography) was
3H), 4.54 (d, J = 15.2 Hz, 1H), 4.18 – 4.05 (m, 1H), 3.98 – 3.72
13
(m, 2H), 3.69 – 3.48 (m, 2H). C NMR (75 MHz, CDCl ) δ
3
168.13, 136.37, 132.96, 131.02, 127.96, 127.37, 119.04, 71.60,
66.90, 60.03, +46.60. HRMS (ESI) m/z Calculated for
+
C H BrN NaO [M
+
Na] 348.9907, 350.9886, found
11
11
4
3
348.9909, 350.9890.
.2.2.4 19dα and 19dβ
Inseparable mixture, yellow oil (total 73.1 mg, 86% yield).
4
performed on 60Å (40 – 60 µm) mesh silica gel (SiO ). All
2
reactions were carried out under nitrogen or argon with
anhydrous solvents in oven-dried glassware, unless otherwise
noted. All reagents were commercially obtained and, where
appropriate, purified prior to use.
The area of one alkyl-H peak on the 1,2-oxazinane ring in α
1
isomer was compared with that in β isomer to derive a H NMR
1
ratio of α/β = 7.7 : 1. 19dα: H NMR (400 MHz, CDCl ) δ 7.66
3

6
Tetrahedron
16 MANIn
–
7.61 (m, 2H), 7.43 – 7.35 (m, 2H), 4.37 – 4
A
.2
C
8 (
C
m
E
, 1
P
H
T
),
E
4.
D
U
se
S
pa
C
ra
R
bleIP
mixture, yellow oil (total 53.0 mg, 72% yield).
T
(dd, J = 11.6, 3.5 Hz, 1H), 3.99 – 3.82 (m, 2H), 3.78 – 3.69 (m,
The area of one alkyl-H peak on the 1,2-oxazinane ring in α
13
1
1
H), 3.69 – 3.62 (m, 1H), 3.61 – 3.52 (m, 1H). C NMR (100
isomer was compared with that in β isomer to derive a H NMR
ratio of α/β = 14.2 : 1. 19hα: H NMR (400 MHz, CDCl ) 4.20
(dd, J = 11.0, 3.2 Hz, 1H), 4.05 (dd, J = 13.6, 3.9 Hz, 1H), 3.76 -
3.66 (m, 1H), 3.66 – 3.53 (m, 2H), 3.47 (s, 1H), 3.39 - 3.28 (m,
1H), 1.47 (s, 9H). C NMR (101 MHz, CDCl ) δ 155.17, 82.74,
69.88, 67.59, 60.94, 50.09, 28.29. 19hβ: H NMR (400 MHz,
1
MHz, CDCl ) δ 169.50, 137.81, 130.66, 130.44, 128.43, 71.32,
3
3
1
6
7
6.89, 59.99, 47.68. 19dβ: H NMR (400 MHz, CDCl ) δ 7.66 –
.61 (m, 2H), 7.43 – 7.35 (m, 2H), 4.53 – 4.43 (m, 1H), 4.08 (dd,
3
13
J = 11.5, 3.9 Hz, 1H), 3.99 – 3.82 (m, 2H), 3.78 – 3.69 (m, 1H),
3
13
1
3
.69 – 3.62 (m, 1H), 3.61 – 3.52 (m, 1H). C NMR (100 MHz,
CDCl ) δ 169.50, 137.81, 130.66, 130.44, 128.43, 71.32, 66.89,
CDCl ) δ 4.29 (dd, J = 11.8, 4.0 Hz, 1H), 4.05 (dd, J = 13.6, 3.9
3
3
5
9.99,
47.68.
HRMS+ (ESI)
m/z
Calculated
for
Hz, 1H), 3.76 - 3.66 (m, 1H), 3.66 – 3.53 (m, 2H), 3.47 (s, 1H),
+
13
C H ClN NaO [M + Na] 305.0412, found 305.0411.
3.39 - 3.28 (m, 1H), 1.47 (s, 9H). C NMR (101 MHz, CDCl ) δ
11
11
4
3
3
1
55.17, 82.74, 69.88, 67.59, 60.94, 50.09, 28.29. HRMS (ESI)
4
.2.2.5 19eα and 19eβ
Inseparable mixture, yellow oil (total 69.0mg, 93% yield). The
+ +
m/z Calculated for C H N NaO [M + Na] 267.1064, found
9
16
4
4
267.1069.
.3. Cyanide addition
4.3.1. Procedure
area of one alkyl-H peak on the 1,2-oxazinane ring in α isomer
was compared with that in β isomer to derive a H NMR ratio of
α/β = 6.7 : 1. 19eα: H NMR (300 MHz, CDCl ) δ 7.79 – 7.67 (m,
4
1
1
3
4
3
3
1
4
4
3
3
1
H), 4.30 (d, J = 13.2 Hz, 1H), 4.16 (dd, J = 11.4, 2.6 Hz, 1H),
To a 10 mL sealed tube equipped with a stir bar were added
i
.98 – 3.85 (m, 1H), 3.80 – 3.70 (m, 1H), 3.70 – 3.62 (m, 1H),
La(OTf) (17.6 mg, 30.0 ꢁmol), Pr-PHOX (13.4 mg, 36.0 ꢁmol),
18 (0.3 mmol), TMSCN (89.3 mg, 0.9 mmol) and anhydrous
DCM (1.0 mL). Then the solution was evacuated and refilled
with N three times and stirred for 4 - 7 days at reflux. When
completed as indicated by TLC, the reaction mixture was
concentrated in vacuo. TBAF (0.45 mL, 1.0 M, 0.45mmol) and
THF (1.0 mL) was added and the reaction mixture was stirred for
3
13
.62 – 3.52 (m, 1H). C NMR (75 MHz, CDCl ) δ 168.37,
3
36.84, 132.02, 129.37, 118.07, 114.81, 71.48, 66.65, 59.84,
1
7.51. 19eβ: H NMR (300 MHz, CDCl ) δ 7.79 – 7.67 (m, 4H),
3
2
.46 (d, J = 9.6 Hz, 1H), 4.07 (dd, J = 12.2, 3.0 Hz, 1H), 3.98 –
.85 (m, 1H), 3.80 – 3.70 (m, 1H), 3.70 – 3.62 (m, 1H), 3.62 –
13
.52 (m, 1H). C NMR (75 MHz, CDCl ) δ 168.37, 136.84,
3
32.02, 129.37, 118.07, 114.81, 71.48, 66.65, 59.84, 47.51.
5
min. The solution was diluted with ethyl acetate (10.0 mL) and
+
+
HRMS (ESI) m/z Calculated for C H ClN NaO [M + Na]
2
12
11
5
3
extracted with ethyl acetate (3 x 50.0 mL). The combined organic
layers were dried over anhydrous Na SO , filtered and
96.0754, found 296.0752.
2
4
concentrated under vacuum. Purification via flash column
chromatography with silica gel (eluting with PE/EA = 2/1 (v/v))
yielded 20α and 20β
4
.2.2.6 19fα and 19fβ
Inseparable mixture, yellow oil (total 75.2 mg, 66% yield).
The area of one alkyl-H peak on the 1,2-oxazinane ring in α
4
.3.2. Characterization of 20
1
isomer was compared with that in β isomer to derive a H NMR
1
4.3.2.1 20aα and 20aβ
ratio of α/β = 5.0 : 1. 19fα: H NMR (400 MHz, CDCl ) δ 8.26 (d,
3
J = 8.7 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 4.32 (d, J = 12.9 Hz,
Inseparable mixture, white solid (total 40.7 mg, 58% yield);
m.p. 98-99 C. The area of one alkyl-H peak on the 1,2-
o
1
1
H), 4.18 (d, J = 9.3Hz1H), 4.04 – 3.90 (m, 1H), 3.89 – 3.77 (m,
H), 3.76 – 3.64 (m, 1H), 3.64 – 3.55 (m, 1H). C NMR (101
13
oxazinane ring in α isomer was compared with that in β isomer to
1
1
derive a H NMR ratio of α/β = 4.2 : 1. 20aα: H NMR (300
MHz, CDCl ) δ 168.32, 149.41, 138.55, 129.94, 123.44, 71.55,
3
1
MHz, CDCl ) δ 7.72 – 7.62 (m, 2H), 7.58 – 7.47 (m, 1H), 7.48 –
3
6
6.81, 59.89, 47.41. 19fβ: H NMR (400 MHz, CDCl ) δ 8.26 (d,
3
7
3
.38 (m, 2H), 4.30 (dd, J = 11.7, 3.5 Hz, 1H),4.26 – 4.09 (m, 2H),
J = 8.7 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 4.47 (d, J = 11.6Hz,
H), 4.10 (d, J = 12.3Hz 1H), 4.04 – 3.90 (m, 1H), 3.89 – 3.77
13
.97 – 3.85 (m, 2H), 3.01 – 2.89 (m, 1H). C NMR (75 MHz,
1
CDCl ) δ 170.99, 132.26, 131.86, 128.88, 128.34, 117.45, 69.08,
13
3
(m, 1H), 3.76 – 3.64 (m, 1H), 3.64 – 3.55 (m, 1H). C NMR
101 MHz, CDCl ) δ 168.32, 149.41, 138.55, 129.94, 123.44,
1
6
4.38, 48.55, 34.27. 20aβ: H NMR (300 MHz, CDCl ) δ 7.72 –
3
(
3
7.62 (m, 2H), 7.58 – 7.47 (m, 1H), 7.48 – 7.38 (m, 2H),4.53 (dd,
J = 13.7, 3.9 Hz, 1H). 4.26 – 4.09 (m, 2H), 3.85 – 3.75 (m, 1H),
7
1.55, 66.81, 59.89, 47.41. HRMS (ESI) m/z Calculated for
+
+
13
C H N NaO [M + Na] 316.0652, found 316.0651.
3.62 – 3.53 (m, 1H),3.01 – 2.89 (m, 1H). C NMR (75 MHz,
11
11
5
5
CDCl ) δ 170.99, 132.26, 131.97, 128.95, 128.34, 117.45, 74.33,
3
4
.2.2.7 19gα and 19gβ
6
5.51, 48.55, 33.48. + HRMS (ESI) m/z Calculated for
+
Inseparable mixture, yellow oil (total 72.6 mg, 87% yield).
C H15NNaO [M + Na] 255.0740, found 255.0735.
14 2
The area of one alkyl-H peak on the 1,2-oxazinane ring in α
1
4.3.2.2 20bα
isomer was compared with that in β isomer to derive a H NMR
1
o
1
ratio of α/β = 8.5 : 1. 19gα: H NMR (400 MHz, CDCl ) δ 7.40 –
White solid (α only, 63.7 mg, 81%); m.p. 132-133 C. H
NMR (400 MHz, DMSO) δ 7.64 (d, J = 8.8 Hz, 2H), 7.00 (d, J =
8.9 Hz, 2H), 5.94 (s, 1H), 4.33 (dd, J = 13.4, 3.8 Hz, 1H), 4.05
(dd, J = 11.4, 3.8 Hz, 1H), 3.96 (td, J = 7.6, 3.9 Hz, 1H), 3.83 –
3.71 (m, 4H), 3.52 (dd, J = 11.3, 7.5 Hz, 1H), 3.05 (td, J = 8.1,
3
7
.22 (m, 1H), 5.12 (s, 1H), 4.17 (dd, J = 11.7, 3.8 Hz, 1H), 4.03
(dd, J = 13.6, 3.6 Hz, 1H), 3.70 – 3.54 (m, 1H), 3.54 – 3.46 (m,
13
1
1
1
1
1
1
1
H), 3.44 – 3.32 (m, 1H). C NMR (101 MHz, CDCl ) δ 155.76,
3
35.51, 128.69, 128.56, 128.20, 70.24, 68.32, 67.16, 60.51, 49.78.
1
13
9gβ: H NMR (400 MHz, CDCl ) δ 7.40 – 7.22 (m, 1H), 5.12 (s,
4.1 Hz, 1H). C NMR (75 MHz, DMSO) δ 168.70, 161.66,
3
H), 4.27 (dd, J = 12.1, 5.0 Hz, 1H), 4.03 (dd, J = 13.6, 3.6 Hz,
130.75, 124.52, 118.99, 113.41, 74.05, 64.28, 55.34, 42.82, 32.68.
+
+
H), 3.70 – 3.54 (m, 1H), 3.54 – 3.46 (m, 1H), 3.44 – 3.32 (m,
HRMS (ESI) m/z Calculated for C H N NaO [M +Na]
13 14 2 4
13
H). C NMR (101 MHz, CDCl ) δ 155.76, 135.51, 128.69,
285.0846, found 285.0846.
3
28.56, 128.20, 70.24, 68.32, 67.16, 60.51, 49.78. HRMS (ESI)
+
+
4.4. Amine addition
m/z Calculated for C H NaN O [M + Na] 301.0907, found
12
14
4
4
3
01.0906.
4
.4.1. Procedure
To a 10 mL sealed tube equipped with a stir bar were added
Cr-II (22.0mg, 30.0 ꢁmol), 18 (0.3 mmol), amine (0.6 mmol)
4
.2.2.8 19hα and 19hβ

7
and anhydrous DME (1.0 mL). Then the soluti
A
on
C
w
C
as
E
e
P
va
T
cu
E
at
D
ed MA
M
N
Hz
U
, C
S
D
C
C
R
l )
I
δ 170.49, 147.07, 136.04, 132.91, 131.29, 128.74,
P
T
3
and refilled with N three times and stirred for 3 - 10 days at 40
128.06, 121.45, 117.79, 110.53, 109.85, 74.35, 67.60, 55.48,
53.46, 47.85. HRMS (ESI) m/z Calculated for C H N NaO [M
2
o
+
C. When completed as indicated by TLC, the reaction mixture
18
20
2
4
+
was concentrated in vacuo. The reaction mixture was purified via
flash column chromatography with silica gel (eluting with PE/EA
+ Na] 351.1315, found 351.1312.
4
.4.2.4 21dα and 21dβ
=
2/1 (v/v)) to yield 21α and 21β
Inseparable mixture, yellow viscous liquid (total 87.0 mg,
3% yield). The area of one alkyl-H peak on the 1,2-oxazinane
4
4
.4.2. Characterization of 21
.4.2.1 21aα and 21aβ
9
ring in α isomer was compared with that in β isomer to derive a
1
1
H NMR ratio of α/β = 7.0 : 1. 21dα: H NMR (400 MHz, CDCl )
Inseparable mixture, yellow viscous liquid (total 72.0 mg,
1% yield). The area of one alkyl-H peak on the 1,2-oxazinane
3
8
δ 7.73 – 7.64 (m, 2H), 7.51 – 7.45 (m, 1H), 7.43 – 7.37 (m, 2H),
6.98 (d, J = 8.2 Hz, 2H), 6.66 – 6.54 (m, 2H), 4.38 (d, J = 9.2 Hz,
ring in α isomer was compared with that in β isomer to derive a
1
1
1
H), 4.26 – 4.11 (m, 1H), 3.98 – 3.82 (m, 2H), 3.81 – 3.65 (m,
H NMR ratio of α/β = 8.0 : 1. 21aα: H NMR (400 MHz,
CDCl ) δ 7.69 (t, J = 9.3 Hz, 2H), 7.48 (t, J = 7.0 Hz, 1H), 7.40
13
2H), 3.64 – 3.58 (m, 1H), 3.58 – 3.53 (m, 1H), 2.24 (s,3H).
C
3
(t, J = 7.3 Hz, 2H), 7.17 (t, J = 7.4 Hz, 2H), 6.74 (t, J = 7.2 Hz,
NMR (75 MHz, CDCl
3
) δ 170.66, 143.78, 133.05, 131.32,
1
30.11, 128.76, 128.15, 113.69, 73.00, 65.87, 53.64, 48.04, 20.46.
1
4
H), 6.65 (d, J = 7.5 Hz, 2H), 4.40 (d, J = 10.0 Hz, 1H), 4.25 –
.08 (m, 1H), 4.05 – 3.87 (m, 2H), 3.68 – 3.55 (m, 2H). C NMR
13
1
21dβ: H NMR (400 MHz, CDCl
7.45 (m, 1H), 7.43 – 7.37 (m, 2H), 6.98 (d, J = 8.2 Hz, 2H), 6.66
6.54 (m, 2H), 4.56 (d, J = 11.4 Hz, 1H), 4.26 – 4.11 (m, 1H),
3.98 – 3.82 (m, 2H), 3.81 – 3.65 (m, 2H), 3.64 – 3.58 (m, 1H),
) δ 7.73 – 7.64 (m, 2H), 7.51 –
3
(75 MHz, CDCl ) δ 170.79, 146.14, 133.01, 131.38, 129.68,
3
–
1
28.79, 128.18, 118.61, 113.40, 72.95, 65.76, 53.15, 47.96. 21aβ:
1
H NMR (400 MHz, CDCl ) δ 7.69 (t, J = 9.3 Hz, 2H), 7.48 (t, J
3
13
=
7.0 Hz, 1H), 7.40 (t, J = 7.3 Hz, 2H), 7.17 (t, J = 7.4 Hz, 2H),
.74 (t, J = 7.2 Hz, 1H), 6.65 (d, J = 7.5 Hz, 2H), 4.56 (d, J =
2.0 Hz, 1H), 4.25 – 4.08 (m, 1H), 4.05 – 3.87 (m, 2H), 3.68 –
3.58 – 3.53 (m, 1H), 2.24 (s,3H). C NMR (75 MHz, CDCl
70.66, 143.78, 132.90, 131.44, 130.11, 128.89, 127.94, 114.01,
74.48, 67.67, 54.42, 48.04, 20.46. HRMS (ESI) m/z Calculated
) δ
3
1
6
1
3
1
6
13
+
+
.55 (m, 2H). C NMR (75 MHz, CDCl ) δ 170.79, 146.14,
for C18H N NaO [M + Na] 335.1366, found 335.1376.
20 2 3
3
33.01, 131.52, 129.68, 128.94, 128.18, 118.94, 113.76, 74.50,
4
.4.2.5 21eα and 21eβ
7.56, 54.06, 47.96. HRMS (ESI) m/z Calculated for
+
+
C H N O [M + H] 299.1390, found 299.1386.
Inseparable mixture, yellow viscous liquid (total 106.0 mg,
4% yield). The area of one alkyl-H peak on the 1,2-oxazinane
ring in α isomer was compared with that in β isomer to derive a
17
19
2
3
8
4
.4.2.2 21bα and 21bβ
1
1
Inseparable mixture, yellow viscous liquid (total 87.4 mg,
9% yield). The area of one alkyl-H peak on the 1,2-oxazinane
H NMR ratio of α/β = 6.0 : 1. 21eα: H NMR (300 MHz, CDCl
δ 7.70 – 7.79 (t, J = 8.4 Hz, 2H), 7.53 – 7.44 (m, 1H), 7.39 (t, J =
.6 Hz, 4H), 6.39 (d, J = 8.6 Hz, 2H), 4.36 (d, J = 10.0 Hz, 1H),
4.24 – 4.05 (m, 2H), 3.99 – 3.79 (m, 2H), 3.69 – 3.54 (m, 1H),
3
)
8
7
ring in α isomer was compared with that in β isomer to derive a
1
1
H NMR ratio of α/β = 11.2 : 1. 21bα: H NMR (400 MHz,
CDCl ) δ 7.71 – 7.63 (m, 1H), 7.53 – 7.43 (m, 1H), 7.43 – 7.34
1
3
3.54 – 3.47 (m, 1H). C NMR (75 MHz, CDCl
45.94, 138.10, 132.79, 131.45, 128.64, 128.21, 115.33, 78.91,
72.66, 65.27, 52.77, 47.96. 21eβ: H NMR (300 MHz, CDCl
7.70 – 7.79 (t, J = 8.4 Hz, 2H), 7.53 – 7.44 (m, 1H), 7.39 (t, J =
.6 Hz, 4H), 6.39 (d, J = 8.6 Hz, 2H), 4.46 (d,J = 9.1 Hz, 1H),
4.24 – 4.05 (m, 2H), 3.99 – 3.79 (m, 2H), 3.69 – 3.54 (m, 1H),
3.54 – 3.47 (m, 1H). C NMR (75 MHz, CDCl
46.14, 138.10, 132.54, 131.62, 128.83, 128.21, 115.50, 79.11,
74.39, 67.13, 53.50, 46.49. HRMS (ESI) m/z Calculated for
) δ 170.58,
3
3
1
(m, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.62 (d, J = 8.7 Hz, 1H), 4.35
1
(d, J = 9.1 Hz, 1H), 4.27 – 4.17 (m, 1H), 3.94 – 3.83 (m, 1H),
3
) δ
13
3
.73 (s, 2H), 3.63 – 3.55 (m, 1H), 3.52 – 3.46 (m, 1H). C NMR
7
(75 MHz, CDCl ) δ 170.59, 152.95, 140.06, 133.03, 131.31,
3
1
2
7
28.74, 128.14, 115.22, 115.19, 73.05, 66.01, 55.85, 54.51, 48.06.
1
13
1aβ: H NMR (400 MHz, CDCl ) δ 7.71 – 7.63 (m, 1H), 7.53 –
3
) δ 170.58,
3
1
.43 (m, 1H), 7.43 – 7.34 (m, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.62
(d, J = 8.7 Hz, 1H), 4.57 (d, J = 11.7 Hz, 1H), 4.27 – 4.17 (m,
+
+
1
–
1
6
H), 3.94 – 3.83 (m, 1H), 3.73 (s, 2H), 3.63 – 3.55 (m, 1H), 3.52
C H17IN NaO [M + Na] 447.0176, found 447.0182.
17 2 3
13
3.46 (m, 1H). C NMR (75 MHz, CDCl ) δ 170.59, 153.18,
3
4
.4.2.6 21fα and 21fβ
39.89, 132.87, 131.43, 128.87, 128.14, 115.62, 115.55, 74.50,
7.80, 55.85, 55.19, 48.06. HRMS (ESI) m/z Calculated for
Inseparable mixture, yellow viscous liquid (total 94.0 mg,
94% yield). The area of one alkyl-H peak on the 1,2-oxazinane
+
+
C H N O [M + H] 329.1496, found 329.1492.
18
21
2
4
ring in α isomer was compared with that in β isomer to derive a
4
.4.2.3 21cα and 21cβ
1
1
H NMR ratio of α/β = 5.5 : 1. 21fα: H NMR (400 MHz, CDCl )
3
Inseparable mixture, yellow viscous liquid (total 88.4 mg,
δ 7.72 – 7.59 m, 2H), 7.72 – 7.59 (m, 1H), 7.39 (t, J = 7.6 Hz,
H), 7.08 (d, J = 8.3 Hz, 2H), 6.60 – 6.47 (m, 2H), 4.37 (d,J =
10.4 Hz, 1H), 4.21 – 4.10 (m, 2H), 3.99 – 3.77 (m, 2H), 3.70 –
2
8
9% yield). The area of methyl peak of methoxyl group in α
1
isomer was compared with that in β isomer to derive a H NMR
1
13
ratio of α/β= 3.8 : 1. 21cα: H NMR (400 MHz, CDCl ) δ 7.69 (d,
3.55 (m, 1H), 3.51 (s, 1H). C NMR (75 MHz, CDCl
3
) δ 170.56,
3
1
44.89, 132.81, 131.43, 129.37, 128.63, 128.20, 122.74, 114.25,
J = 7.2 Hz, 2H), 7.52 – 7.44 (m, 1H), 7.44 - 7.37 (m, 2H), 6.88 –
1
6
6
1
1
1
1
.82 (m, 1H), 6.81 – 6.76 (m, 1H), 6.76 – 6.71 (m, 1H), 6.70 –
.65 (m, 1H), 4.60 (s, 1H), 4.43 (d, J = 11.1 Hz, 1H), 4.17 (d, J =
2.3 Hz, 1H), 4.05 – 3.90 (m, 2H), 3.83 (s,3H), 3.72 – 3.64 (m,
72.73, 65.35, 53.07, 47.92. 21fβ: H NMR (400 MHz, CDCl
7.72 – 7.59 m, 2H), 7.72 – 7.59 (m, 1H), 7.39 (t, J = 7.6 Hz, 2H),
.08 (d, J = 8.3 Hz, 2H), 6.60 – 6.47 (m, 2H), 4.37 (d, J = 10.4
Hz, 1H), 4.21 – 4.10 (m, 2H), 3.99 – 3.77 (m, 2H), 3.70 – 3.55
3
) δ
7
13
H), 3.59 (s, 1H). C NMR (75 MHz, CDCl ) δ 170.49, 146.92,
3
13
35.95, 133.06, 131.18, 128.67, 128.06, 121.34, 117.54, 110.27,
(m, 1H), 3.51 (s, 1H). C NMR (75 MHz, CDCl
45.09, 132.58, 131.59, 129.37, 128.81, 128.20, 122.86, 114.42,
74.40, 67.21, 53.77, 47.92. HRMS (ESI) m/z Calculated for
3
) δ 170.82,
1
1
09.85, 72.87, 65.45, 55.42, 52.59, 47.85. 21cβ: H NMR (400
MHz, CDCl ) δ 7.69 (d, J = 7.2 Hz, 2H), 7.52 – 7.44 (m, 1H),
3
+
+
7
6
=
.44 - 7.37 (m, 2H), 6.88 – 6.82 (m, 1H), 6.81 – 6.76 (m, 1H),
.76 – 6.71 (m, 1H), 6.70 – 6.65 (m, 1H), 4.60 (s, 1H), 4.43 (d, J
C H17ClN NaO [M + Na] 355.0820, found 355.0826.
17 2 3
4
.4.2.7 21gα and 21gβ
11.1 Hz, 1H), 4.17 (d, J = 12.3 Hz, 1H), 4.05 – 3.90 (m, 2H),
13
3
.84 (s,3H), 3.72 – 3.64 (m, 1H), 3.59 (s, 1H). C NMR (75
Inseparable mixture, yellow viscous liquid (total 51.0 mg,
4% yield). The area of one alkyl-H peak on the 1,2-oxazinane
5

8
Tetrahedron
ring in α isomer was compared with that in β
A
iso
C
m
C
er
E
to
P
d
T
erive
E
D
a
MA23
NU
6.
2 H
S
z
C
),
R
14
I
2.60 (d, J = 2.0 Hz), 131.22, 124.71, 116.03 (d, J =
P
T
1
1
H NMR ratio of α/β = 5.0 : 1. 21gα: H NMR (400 MHz, CDCl )
22.4 Hz), 114.41 (d, J = 7.4 Hz), 113.42, 72.85, 65.85, 55.44,
3
1
δ 7.75 – 7.61 (m, 2H), 7.54 – 7.44 (m, 1H), 7.44 – 7.35 (m, 2H),
54.05, 48.14. 21jβ: H NMR (400 MHz, CDCl ) δ 7.77 – 7.65 (m,
3
6
1
1
1
1
7
7
6
1
1
1
1
7
.93 – 6.80 (m, 2H), 6.65 – 6.51 (m, 2H), 4.37 (d, J = 9.2 Hz,
2H), 6.92 – 6.80 (m, 4H), 6.65 – 6.52 (m, 2H), 4.52 (d, J = 7.3
H), 4.26 – 4.12 (m, 1H), 4.04 – 3.80 (m 2H), 3.69 – 3.58 (m,
Hz 1H), 4.25 – 4.15 (m, 1H), 3.96 – 3.85 (m, 2H), 3.85 – 3.79 (m,
13
13
H), 3.53 – 3.47 (m, 1H). C NMR (101 MHz, CDCl ) δ 170.68,
3H), 3.69 – 3.55 (m, 1H), 3.54 – 3.45 (m, 1H). C NMR (75
3
56.28 (d, J = 236.3 Hz), 142.56 (d, J = 1.9 Hz), 132.94, 131.41,
MHz, CDCl ) δ 170.38, 162.21, 156.27 (d, J = 236.2 Hz), 142.60
3
28.72, 128.19, 116.06 (d, J = 22.4 Hz), 114.36 (d, J = 7.4 Hz),
(d, J = 2.0 Hz), 131.37, 124.71, 116.03 (d, J = 22.4 Hz), 114.63
(d, J = 7.5 Hz), 113.42, 74.41, 65.85, 55.44, 54.05, 48.14. HRMS
1
2.94, 65.72, 53.86, 48.04. 21gβ: H NMR (400 MHz, CDCl ) δ
3
+
+
.75 – 7.61 (m, 2H), 7.54 – 7.44 (m, 1H), 7.44 – 7.35 (m, 2H),
.93 – 6.80 (m, 2H), 6.65 – 6.51 (m, 2H), 4.54 (d, J = 9.1 Hz,
H), 4.26 – 4.12 (m, 1H), 4.04 – 3.80 (m 2H), 3.69 – 3.58 (m,
(ESI) m/z Calculated for C H FN NaO [M + Na] 369.1221,
18 19 2 4
found 369.1230.
13
4.4.2.11 21kα and 21kβ
H), 3.53 – 3.47 (m, 1H). C NMR (101 MHz, CDCl ) δ 170.68,
3
56.28 (d, J = 236.3 Hz), 142.56 (d, J = 1.9 Hz), 132.74, 131.55,
28.88, 128.19, 116.06 (d, J = 22.4 Hz), 114.55 (d, J = 7.6 Hz),
4.48, 67.58, 54.52, 48.04. HRMS (ESI) m/z Calculated for
Inseparable mixture, yellow viscous liquid (total 106.0 mg,
91% yield). The area of one alkyl-H peak on the 1,2-oxazinane
ring in α isomer was compared with that in β isomer to derive a
+
+
1
1
C H FN O [M + H] 317.1296, found 317.1293.
H NMR ratio of α/β = 4.9 : 1. 21kα: H NMR (400 MHz,
CDCl ) δ 7.76 – 7.68 (m, 2H), 6.92 – 8.65 (m, 2H), 6.61 (d,J =
17
18
2
3
3
4
.4.2.8 21hα and 21hβ
8
.6 Hz, 1H), 6.47– 6.42 (m, 1H), 6.41 – 6.34 (m, 1H), 4.35 (dd, J
Inseparable mixture, yellow viscous liquid (total 97.0 mg,
3% yield). The area of one alkyl-H peak on the 1,2-oxazinane
= 11.4, 2.6 Hz,1H), 4.28 – 4.15 (m, 1H), 3.94 – 3.84 (m, 2H),
3.82 (s, 3H), 3.79 (s, 3H), 3.73 (s, 3H), 3.64 – 3.58 (m, 1H), 3.3 –
9
13
ring in α isomer was compared with that in β isomer to derive a
3.47 (m, 1H). C NMR (75 MHz, CDCl ) δ 170.33, 162.07,
3
1
1
H NMR ratio of α/β = 7.9 : 1. 21hα: H NMR (300 MHz,
CDCl ) δ 8.22 (d, J = 8.7 Hz, 2H), 7.81 (d, J = 8.3 Hz, 2H), 7.17
152.84, 148.49, 131.23, 130.04, 124.97, 113.31, 111.84, 104.10,
1
99.47, 73.03, 66.19, 55.83, 55.57, 55.41, 54.24, 48.06. 21kβ: H
3
(t, J = 7.7 Hz, 2H), 6.75 (t, J = 7.3 Hz, 1H), 6.64 (d, J = 7.9 Hz,
NMR (400 MHz, CDCl ) δ 7.76 – 7.68 (m, 2H), 6.92 – 8.65 (m,
3
2
H), 4.39 (d, J = 9.6 Hz, 1H), 4.26 – 4.12 (m, 1H), 4.07 – 3.93
2H), 6.72 (d, J = 8.5 Hz, 1H), 6.47– 6.42 (m, 1H), 6.41 – 6.34 (m,
1H), 4.61 (d, J =10.5, 1H), 4.28 – 4.15 (m, 1H), 3.94 – 3.84 (m,
13
(m, 2H), 3.71 – 3.55 (m, 2H). C NMR (75 MHz, CDCl ) δ
3
1
1
68.09, 149.10, 145.97, 138.97, 129.68, 129.65, 123.31, 118.64,
13.22, 73.24, 65.27, 52.71, 47.38. 21hβ: H NMR (300 MHz,
2H), 3.83 (s, 3H), 3.80 (s, 3H), 3.73 (s, 3H), 3.64 – 3.58 (m, 1H),
1
13
3.3 – 3.47 (m, 1H). C NMR (75 MHz, CDCl ) δ 170.18, 162.13,
3
CDCl ) δ 8.22 (d, J = 8.7 Hz, 2H), 7.81 (d, J = 8.3 Hz, 2H), 7.17
153.07, 148.69, 131.23, 129.97, 124.93, 113.31, 112.23, 104.18,
99.47, 74.38, 68.27, 55.83, 55.60, 55.41, 54.83, 47.05. HRMS
3
(t, J = 7.7 Hz, 2H), 6.75 (t, J = 7.3 Hz, 1H), 6.64 (d, J = 7.9 Hz,
+
+
2
H), 4.62 (d, J = 11.2 Hz, 1H), 4.26 – 4.12 (m, 1H), 4.07 – 3.93
(ESI) m/z Calculated for C H N O [M + H] 389.1707, found
20 25 2 6
13
(m, 2H), 3.71 – 3.55 (m, 2H). C NMR (75 MHz, CDCl ) δ
389.1707.
.4.2.12 21lα and 21lβ
Inseparable mixture, yellow viscous liquid (total 72.0mg, 70%
3
1
1
68.09, 149.21, 146.20, 138.63, 129.89, 129.26, 123.31, 118.87,
4
13.49, 73.24, 67.37, 53.64, 47.38. HRMS (ESI) m/z Calculated
+
+
for C H N NaO [M + H] 366.1060, found 366.1059.
17
17
3
5
yield). The area of one alkyl-H peak on the 1,2-oxazinane ring in
4
.4.2.9 21iα and 21iβ
1
α isomer was compared with that in β isomer to derive a H NMR
1
Inseparable mixture, yellow viscous liquid (total 88.0 mg,
9 % yield). The area of one alkyl-H peak on the 1,2-oxazinane
ratio of α/β = 5.0 : 1. 21lα: H NMR (300 MHz, CDCl ) δ 7.66 (d,
3
8
J = 8.7 Hz, 2H), 7.33 – 7.17 (m, 5H), 6.89 – 6.80 (m, 2H), 4.41
(d, J = 12.7 Hz, 1H), 4.17 – 3.99 (m, 1H), 3.84 – 3.70 (m, 5H),
3.70 – 3.62 (m, 1H), 3.49 – 3.29 (m, 2H), 2.86 – 2.78 (m, 1H).
ring in α isomer was compared with that in β isomer to derive a
1
1
H NMR ratio of α/β = 9.1 : 1. 21iα: H NMR (400 MHz, CDCl )
3
13
δ 7.78 – 7.69 (m, 2H), 7.16 (t, J = 7.8 Hz, 2H), 6.93 – 6.85 (m,
C NMR (75 MHz, CDCl ) δ 170.02, 162.08, 139.89, 131.25,
3
2
7
H), 6.73 (t, J = 7.3 Hz, 1H), 6.78 – 6.59 (m, 2H), 4.39 (d, J =
128.71, 128.13, 127.43, 124.92, 113.32, 73.51, 67.79, 58.65,
1
.8 Hz,1H), 4.26 – 4.16 (m, 1H), 4.13 – 3.98 (m, 1H), 3.97 – 3.87
55.46, 51.73, 48.68. 21lβ: H NMR (300 MHz, CDCl ) δ 7.66 (d,
3
13
(m, 2H), 3.84 – 3.81 (m, 3H), 3.65 – 3.55 (m, 2H). C NMR (75
J = 8.7 Hz, 2H), 7.33 – 7.17 (m, 5H), 6.89 – 6.80 (m, 2H), 4.62
(d, J = 13.2 Hz, 1H), 4.17 – 3.99 (m, 1H), 3.84 – 3.70 (m, 5H),
MHz, CDCl ) δ 170.33, 162.15, 146.33, 131.21, 129.59, 124.80,
3
1
18.38, 113.39, 113.32, 72.86, 65.82, 55.43, 53.27, 48.15. 21iβ:
3.70 – 3.62 (m, 1H), 3.49 – 3.29 (m, 2H), 2.86 – 2.78 (m, 1H).
1
13
H NMR (400 MHz, CDCl ) δ 7.78 – 7.69 (m, 2H), 7.16 (t, J =
C NMR (75 MHz, CDCl ) δ 169.63, 162.08, 139.76, 131.16,
3
3
7
.8 Hz, 2H), 6.93 – 6.85 (m, 2H), 6.73 (t, J = 7.3 Hz, 1H), 6.78 –
.59 (m, 2H), 4.39 (d, J = 7.8 Hz,1H), 4.26 – 4.16 (m, 1H), 4.13
3.98 (m, 1H), 3.97 – 3.87 (m, 2H), 3.84 – 3.81 (m, 3H), 3.65 –
128.71, 128.28, 127.43, 124.92, 113.32, 74.36, 68.92, 58.09,
6
–
3
1
6
55.46, 51.19,+ 48.68. HRMS (ESI) m/z Calculated for
+
C H N NaO [M + Na] 365.1472, found 365.1467.
19
22
2
4
13
.55 (m, 2H). C NMR (75 MHz, CDCl ) δ 170.54, 162.25,
3
4
.4.2.13 21mα and 21mβ
46.43, 131.34, 129.59, 124.69, 118.51, 113.52, 113.32, 74.40,
7.45, 55.43, 53.81, 46.71. HRMS (ESI) m/z Calculated for
Inseparable mixture, yellow viscous liquid (total 60.0mg, 83%
+
+
C H N NaO [M + Na] 351.1315, found 351.1322.
yield). The area of one alkyl-H peak on the 1,2-oxazinane ring in
18
20
2
4
1
α isomer was compared with that in β isomer to derive a H NMR
4
.4.2.10 21jα and 21jβ
1
ratio of α/β = 4.0 : 1. 21mα: H NMR (400 MHz, CDCl ) δ 7.68
3
Inseparable mixture, yellow viscous liquid (total 93.0 mg,
0% yield). The area of one alkyl-H peak on the 1,2-oxazinane
(d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.88 – 5.75 (m, 1H),
5.23– 5.05 (m, 2H), 4.46 (d, J = 11.2 Hz, 1H), 4.23 – 4.03 (m,
9
ring in α isomer was compared with that in β isomer to derive a
1H), 3.81 (s, 3H), 3.68 (s, 1H), 3.54 – 3.33 (m, 2H), 3.33 – 3.05
1
1
13
H NMR ratio of α/β = 7.6 : 1. 21jα: H NMR (400 MHz, CDCl )
(m, 2H), 2.99 – 2.69 (m, 1H). C NMR (75 MHz, CDCl ) δ
3
3
δ 7.77 – 7.65 (m, 2H), 6.92 – 6.80 (m, 4H), 6.65 – 6.52 (m, 2H),
169.89, 162.04, 136.43, 131.17, 124.88, 116.65, 113.29, 73.47,
67.57, 58.43, 55.40, 50.14, 48.77. 21mβ: H NMR (400 MHz,
1
4
2
1
.36 (dd, J = 8.5, 1.8 Hz 1H), 4.25 – 4.15 (m, 1H), 3.96 – 3.85 (m,
H), 3.85 – 3.79 (m, 3H), 3.69 – 3.55 (m, 1H), 3.54 – 3.45 (m,
CDCl ) δ 7.68 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.88
3
13
H). C NMR (75 MHz, CDCl ) δ 170.38, 162.21, 156.27 (d, J =
– 5.75 (m, 1H), 5.23– 5.05 (m, 2H), 4.64 (d, J = 11.5 Hz, 1H),
3

9
4
2
.23 – 4.03 (m, 1H), 3.81 (s, 3H), 3.68 (s, 1H
H), 3.33 – 3.05 (m, 2H), 2.99 – 2.69 (m, 1H). C NMR (75
A
),
C
3.5
C
4 –
E
P
3.
T
33
E
(
D
m, MANIn
U
se
S
pa
C
ra
R
bleIP
mixture, yellow viscous liquid (total 77.0mg,
T
1
3
96% yield). The area of one alkyl-H peak on the 1,2-oxazinane
MHz, CDCl ) δ 169.54, 161.98, 136.43, 131.17, 125.04, 116.84,
ring in α isomer was compared with that in β isomer to derive a
H NMR ratio of α/β = 7.2 : 1. 21qα: H NMR (400 MHz,
3
1
1
1
13.29, 74.41, 68.74, 57.86, 55.40, 49.64, 48.77. HRMS (ESI)
+
+
m/z Calculated for C H N O [M + H] 293.1496, found
CDCl ) δ 7.71 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.75
15
21
2
4
3
2
93.1497.
.4.2.14 21nα and 21nβ
Inseparable mixture, yellow viscous liquid (total 40.0mg, 56%
(dd, J = 12.8, 4.6 Hz, 1H), 4.15 (dd, J = 11.2, 4.2 Hz, 1H), 3.91 –
3
1
.81 (m, 4H), 3.76 – 3.64 (m, 6H), 3.27 – 3.19 (m, 1H), 2.96 (s,
H), 2.84 – 2.75 (m, 2H), 2.72 – 2.65 (m, 1H), 2.57 – 2.47 (m,
4
13
2H). C NMR (75 MHz, CDCl
) δ 169.52, 162.07, 131.20,
3
yield). The area of one alkyl-H peak on the 1,2-oxazinane ring in
α isomer was compared with that in β isomer to derive a H NMR
ratio of α/β = 4.6 : 1. 21nα: H NMR (300 MHz, CDCl ) δ 7.70
124.84, 113.29, 74.97, 69.56, 67.42, 66.11, 64.31, 63.66, 55.41,
1
1
49.89, 41.78. 21qβ: H NMR (400 MHz, CDCl ) δ 7.71 (d, J =
3
1
8.7 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.75 (dd, J = 12.8, 4.6 Hz,
1H), 4.15 (dd, J = 11.2, 4.2 Hz, 1H), 3.91 – 3.81 (m, 4H), 3.76 –
3.64 (m, 6H), 3.27 – 3.19 (m, 1H), 2.96 (s, 1H), 2.84 – 2.75 (m,
3
(d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.48 (dd, J = 13.1,
3
3
2
1
4
8
1
1
1
1
3
.6 Hz, 1H), 4.25 (dd, J = 11.4, 4.1 Hz, 1H), 3.83 (s, 3H), 3.78 –
13
.65 (m, 1H), 3.61 – 3.36 (m, 4H), 3.07 – 2.93 (m, 1H), 2.31 –
2H), 2.72 – 2.65 (m, 1H), 2.57 – 2.47 (m, 2H). C NMR (75
MHz, CDCl ) δ 169.81, 162.07, 131.16, 124.88, 113.29, 74.97,
69.56, 67.34, 65.29, 64.31, 63.66, 55.41, 49.26, 41.78. HRMS
13
.22 (m, 1H). C NMR (75 MHz, CDCl ) δ 170.10, 162.15,
3
3
31.29, 124.86, 113.36, 81.76, 73.13, 72.40, 67.72, 58.02, 55.48,
1
+
+
8.67, 36.40. 21nβ: H NMR (300 MHz, CDCl ) δ 7.70 (d, J =
(ESI) m/z Calculated for C16H N HO [M + H] 323.1601, found
23 2 5
3
.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.65 (dd, J = 13.1, 3.8 Hz,
H), 4.21 (dd, J = 11.0, 3.8 Hz, 1H), 3.83 (s, 3H), 3.78 – 3.65 (m,
H), 3.61 – 3.36 (m, 4H), 3.07 – 2.93 (m, 1H), 2.31 – 2.22 (m,
323.1601.
4
.4.2.18 21rα and 21rβ
Inseparable mixture, yellow viscous liquid (total 90.3 mg,
13
H). C NMR (75 MHz, CDCl ) δ 170.10, 162.15, 131.20,
3
25.03, 113.36, 81.59, 74.24, 72.60, 68.69, 57.25, 55.48, 48.67,
85% yield). The area of one alkyl-H peak on the 1,2-oxazinane
+
6.06. HRMS (ESI) m/z Calculated for C H N O [M +
ring in α isomer was compared with that in β isomer to derive a
15
19
2
4
+
1
1
H] 291.1339, found 291.1337.
.4.2.15 21oα and 21oβ
Inseparable mixture, yellow viscous liquid (total 77.0mg, 92%
H NMR ratio of α/β = 4.0 : 1. 21rα: H NMR (400 MHz, CDCl )
3
δ 7.68 (d, J = 8.7 Hz, 2H), 6.93 – 6.80 (m, 2H), 4.72 (dd, J =
2.8, 4.4 Hz, 1H), 4.09 (dd, J = 11.2, 4.2 Hz, 1H), 3.94 – 3.78
4
1
(m, 4H), 3.71 – 3.58 (m, 1H), 3.52 – 3.30 (m, 5H), 3.24 – 3.12
yield). The area of one alkyl-H peak on the 1,2-oxazinane ring in
α isomer was compared with that in β isomer to derive a H NMR
ratio of α/β = 5.0 : 1. 21oα: H NMR (300 MHz, CDCl ) δ 7.77 –
7
4
3
(m, 1H), 2.87 – 2.67 (m, 3H), 2.57 – 2.43 (m, 2H), 1.41 (s, 9H).
1
13
C NMR (75 MHz, CDCl ) δ 169.49, 162.04, 154.55, 131.14,
3
1
124.80, 113.26, 79.90, 74.98, 69.65, 66.15, 63.80, 55.37, 49.34,
1
3
.58 (m, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.53 (d, J = 10.6 Hz, 1H),
44.37, 41.92, 28.39. 21rβ: H NMR (400 MHz, CDCl ) δ 7.68 (d,
3
.23 – 4.04 (m, 3H), 3.82 (s, 3H), 3.73 – 3.62 (m, 1H), 3.57 –
J = 8.7 Hz, 2H), 6.93 – 6.80 (m, 2H), 4.64 (dd, J = 12.9, 4.0 Hz,
1H), 4.14 (dd, J = 10.8, 5.1 Hz, 1H), 3.94 – 3.78 (m, 4H), 3.71 –
3.58 (m, 1H), 3.52 – 3.30 (m, 5H), 3.24 – 3.12 (m, 1H), 2.87 –
13
.26 (m, 4H), 2.79 – 2.67 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H).
C
NMR (75 MHz, CDCl ) δ 173.28, 169.84, 162.04, 131.18,
3
13
1
1
6
3
–
24.97, 113.31, 73.34, 68.00, 61.37, 59.52, 55.43, 49.01, 48.47,
2.67 (m, 3H), 2.57 – 2.43 (m, 2H), 1.43 (s, 9H). C NMR (75
MHz, CDCl ) δ 169.80, 162.04, 154.60, 131.14, 124.80, 113.26,
79.97, 74.98, 69.65, 65.31, 64.44, 55.37, 49.34, 44.37, 41.92,
1
4.24. 21oβ: H NMR (300 MHz, CDCl ) δ 7.77 – 7.58 (m, 2H),
3
3
.87 (d, J = 8.7 Hz, 2H), 4.62 (d, J = 4.0 Hz, 1H), 4.23 – 4.04 (m,
+
+
H), 3.82 (s, 3H), 3.73 – 3.62 (m, 1H), 3.57 – 3.26 (m, 4H), 2.79
28.39. HRMS (ESI) m/z Calculated for C21H N NaO [M + Na]
31 3 6
13
2.67 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H). C NMR (75 MHz,
444.2105, found 444.2104.
CDCl ) δ 173.28, 169.84, 162.04, 131.18, 124.97, 113.31, 73.34,
3
4
.4.2.19 21sα and 21sβ
Inseparable mixture, yellow viscous liquid (total 63.6 mg,
6
8.00, 61.37, 59.52, 55.43, 48.81, 48.47, 14.24. HRMS (ESI) m/z
+
+
Calculated for C H N NaO
[M
+
Na]
361.1370,
16
22
2
6
found361.1364.
.4.2.16 21pα and 21pβ
Inseparable mixture, yellow viscous liquid (total 75.0mg, 94%
69% yield). The area of one alkyl-H peak on the 1,2-oxazinane
ring in α isomer was compared with that in β isomer to derive a
4
1
1
H NMR ratio of α/β = 12.0 : 1. 21sα: H NMR (400 MHz,
CDCl ) δ 7.75 (d, J = 8.8 Hz, 2H), 7.10 – 7.03 (m, 1H), 6.97 (d, J
3
yield). The area of one alkyl-H peak on the 1,2-oxazinane ring in
= 7.1 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.3 Hz, 1H),
6.65 (t, J = 7.3 Hz, 1H), 4.75 (dd, J = 13.0, 4.5 Hz, 1H), 4.19 –
4.04 (m, 2H), 4.04 – 3.97 (m, 1H), 3.84 (s, 3H), 3.77 – 3.69 (m,
1H), 3.43 – 3.32 (m, 2H), 3.16 – 3.09 (m, 1H), 2.75 (t, J = 6.3 Hz,
1
α isomer was compared with that in β isomer to derive a H NMR
1
ratio of α/β = 3.9 : 1. 21pα: H NMR (400 MHz, CDCl ) δ 7.58
3
(d, J = 8.8 Hz, 2H), 6.82 – 6.73 (m, 2H), 4.68 (dd, J = 12.6, 4.8
13
Hz, 1H), 4.08 – 3.97 (m, 1H), 3.81 – 3.65 (m, 4H), 3.40 – 3.26
2H), 1.99 – 1.77 (m, 2H). C NMR (75 MHz, CDCl ) δ 169.65,
3
(
m, 1H), 3.11 – 2.98 (m, 1H), 2.78 – 2.47 (m, 3H), 2.44 – 2.27
162.21, 145.11, 131.35, 129.81, 127.36, 124.71, 123.89, 117.40,
13
(m, 2H), 1.50 – 1.28 (m, 6H). C NMR (75 MHz, CDCl ) δ
113.38, 111.48, 70.21, 64.45, 59.56, 55.48, 49.63, 43.02, 28.13,
3
1
1
6
69.46, 162.05, 131.21, 125.19, 113.34, 69.74, 67.45, 63.61,
0.53, 55.49, 50.70, 26.80, 24.69, 21.19, 14.32. 21pβ: H NMR
22.58. 21sβ: H NMR (400 MHz, CDCl
3
) δ 7.75 (d, J = 8.8 Hz,
1
2H), 7.10 – 7.03 (m, 1H), 6.97 (d, J = 7.1 Hz, 1H), 6.90 (d, J =
8.8 Hz, 2H), 6.82 (d, J = 8.3 Hz, 1H), 6.65 (t, J = 7.3 Hz, 1H),
4.46 (d, J = 15.4 Hz, 1H), 4.19 – 4.04 (m, 2H), 4.04 – 3.97 (m,
(
400 MHz, CDCl ) δ 7.58 (d, J = 8.8 Hz, 2H), 6.82 – 6.73 (m,
3
2
3
2
H), 4.58 (dd, J = 12.8, 4.2 Hz, 1H), 4.08 – 3.97 (m, 1H), 3.81 –
.65 (m, 4H), 3.40 – 3.26 (m, 1H), 3.11 – 2.98 (m, 1H), 2.78 –
1H), 3.84 (s, 3H), 3.77 – 3.69 (m, 1H), 3.43 – 3.32 (m, 2H), 3.16
13
13
.47 (m, 3H), 2.44 – 2.27 (m, 2H), 1.50 – 1.28 (m, 6H). C NMR
– 3.09 (m, 1H), 2.75 (t, J = 6.3 Hz, 2H), 1.99 – 1.77 (m, 2H).
NMR (75 MHz, CDCl
C
(
75 MHz, CDCl ) δ 169.46, 162.05, 131.21, 125.19, 113.34,
3
) δ 169.65, 162.21, 145.11, 131.41,
3
7
1
3
5.39, 66.31, 64.41, 58.57, 55.49, 49.72, 26.74, 24.69, 21.19,
129.81, 127.36, 124.71, 123.89, 117.40, 113.38, 111.48, 70.21,
+
+
4.32. HRMS (ESI) m/z Calculated for C H N NaO [M + Na]
64.45, 59.56, 55.48, 49.63, 43.02, 28.13, 22.58. HRMS (ESI) m/z
17
25
2
4
+
+
21.1809, found 321.1806.
Calculated for
found391.1632.
C
21
H
24
N
2
NaO
5
[M
+
Na]
391.1628,
4
.4.2.17 21qα and 21qβ

1
0
Tetrahedron
o
1
4
.4.2.20 21tα and 21tβ
ACCEPTED MAN
W
U
hi
S
te
C
so
R
li
I
d (72.3 mg, 91% yield); m.p. 60-61 C. H NMR
P
T
(
400 MHz, CDCl ) δ 4.12 (dd, J = 12.0, 4.0 Hz, 1H), 3.70 (td, J =
3
Inseparable mixture, yellow viscous liquid (total 74.0mg, 97%
7
.3, 4.0 Hz, 1H), 3.60 – 3.52 (m, 1H), 3.43 – 3.32 (m, 2H), 2.93
yield). The area of one alkyl-H peak on the 1,2-oxazinane ring in
α isomer was compared with that in β isomer to derive a H NMR
ratio of α/β = 5.3 : 1.21tα: H NMR (300 MHz, CDCl ) δ 7.70
13
1
(dd, J = 12.7, 7.7 Hz, 1H). C NMR (75 MHz, CDCl
67.32, 60.51, 51.86. HRMS (ESI) m/z Calculated for
) δ 68.85,
3
1
3
+
+
C H N O [M + H] 145.0720, found 145.0713.
4
9
4
2
(
1
dd, J = 8.7, 4.5 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.40 (dd, J =
3.1, 3.3 Hz, 1H), 4.18 (dd, J = 11.6, 3.3 Hz, 1H), 4.03 – 3.88
m, 1H), 3.86 – 3.72 (m, 4H), 3.69 – 3.59 (m, 1H), 3.56 – 3.35
4.5.2.2. 23iα
(
(
o
1
13
White solid (62.3 mg, 80% yield); m.p. 134-135 C. H NMR
m, 1H), 2.87 – 2.57 (m, 5H), 1.87 – 1.67 (m, 4H). C NMR (75
(400 MHz, DMSO) δ 7.01 (t, J = 7.9 Hz, 2H), 6.59 (d, J = 7.8 Hz,
MHz, CDCl ) δ 170.15, 161.99, 131.16 (d, J = 8.0 Hz), 125.16,
3
2
H), 6.46 (t, J = 7.2 Hz, 1H), 6.36 – 6.29 (m, 1H), 5.48 (d, J =
1
4
8
13.28, 74.53, 70.16, 66.66, 65.62, 62.89, 55.43, 50.46, 49.66,
2.27, 23.58. 21tβ: H NMR (300 MHz, CDCl ) δ 7.70 (dd, J =
.7, 4.5 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.53 (dd, J = 13.2, 3.7
1
7.4 Hz, 1H), 4.99 (s, 1H), 4.00 (dd, J = 11.3, 4.0 Hz, 1H), 3.49 –
3
3
.41 (m, 1H), 3.26 (dd, J = 11.2, 8.3 Hz, 1H), 3.22 – 3.11 (m,
13
2
H), 2.75 – 2.65 (m, 1H). C NMR (75 MHz, DMSO) δ 153.47,
Hz, 1H), 4.18 (dd, J = 11.6, 3.3 Hz, 1H), 4.03 – 3.88 (m, 1H),
1
34.13, 120.79, 117.36, 76.21, 72.24, 59.89, 58.95. HRMS (ESI)
3
2
.86 – 3.72 (m, 4H), 3.69 – 3.59 (m, 1H), 3.56 – 3.35 (m, 1H),
.87 – 2.57 (m, 5H), 1.87 – 1.67 (m, 4H). C NMR (75 MHz,
+
+
13
m/z Calculated for C H N O [M + H] 145.0720, found 145.0727.
4 9 4 2
CDCl ) δ 169.69, 161.99, 131.16 (d, J = 8.0 Hz), 125.16, 113.28,
3
Acknowledgments
7
2
3
4.53, 70.16, 66.66, 65.62, 61.75, 55.43, 50.46, 48.47, 42.27,
+ +
3.66.HRMS (ESI) m/z Calculated for C H N O [M + H]
16
23
2
4
The authors thank the National Natural Science Foundation of
China (21672027), the QingLan Project of Jiangsu Province
(2016) and the Six-Talent-Peaks Program of Jiangsu (2016) for
financial support. This work was also supported by High-Level
Entrepreneurial Talent Team of Jiangsu Province (2017-37)
07.1652, found307.1647.
4
4
.5. N-Acyl deprotection
.5.1. Procedure
To a 10 mL sealed tube equipped with a stir bar were added
1
9bα or 21iα (0.55 mmol), NaOH (87.0 mg, 2.2 mmol) and
Supplementary Material
anhydrous MeOH (1.0 mL). Then the solution was stirred for 36
hours at room temperature. When completed as indicated by
TLC, The reaction mixture was concentrated under vacuum and
purified via flash column chromatography with silica gel (eluting
with DCM/MeOH = 50/1 (v/v)) to yield 23bα or 23iα.
Supplementary material including experimental details for
substrate synthesis and characterizations, crystal data and
structure refinement and copies of NMR spectra related to this
article can be found online at https://doi.org/xxxxx.
4
4
.5.2. Characterization of 23
.5.2.1. 23bα
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