Stereoselective Synthesis of Pyrido- and Pyrrolo[1,2-c][1,3]oxazin-1-ones via a Nucleophilic Addition-Cyclization Process of N,O-Acetal with Ynamides

Article abstract of DOI:10.1021/acs.joc.8b02795

An efficient asymmetric approach to access functionalized pyrido- and pyrrolo[1,2-c][1,3]oxazin-1-ones has been developed through a nucleophilic addition-cyclization process of N,O-acetal with ynamides. A number of substituted ynamides 8a-8o and 3-silyloxypyrrolidine or piperidine N,O-acetals 6a, 7 were amenable to this transformation, and the desired products 9a-9o, 10a-10m were obtained with excellent regioselectivities and outstanding diastereoselectivities. Moreover, chiral ynamides 14a-14f could also experience this addition-cyclization process to afford products 15a-15f in excellent yields.

Full text of DOI:10.1021/acs.joc.8b02795

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Article
Stereoselective Synthesis of Pyrido and Pyrrolo[1,2-c][1,3]oxazin-1-ones
via Nucleophilic Addition-Cyclization Process of N,O-acetal with Ynamides
Pan Han, Zhuo-Ya Mao, Chang-Mei Si, Zhu Zhou, Bang-Guo Wei, and Guo-Qiang Lin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02795 • Publication Date (Web): 21 Dec 2018
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Stereoselective Synthesis of Pyrido and
Pyrrolo[1,2-c][1,3]oxazin-1-ones via Nucleophilic
8
9
Addition-Cyclization Process of N,O-acetal with Ynamides
Pan Han,† Zhuo-Ya Mao,† Chang-Mei Si,† Zhu Zhou,† Bang-Guo Wei*† and Guo-Qiang Lin†, ‡
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† School of Pharmacy and Institutes of Biomedical Sciences, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
‡ Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
Abstract
R
R
R3
R2
n
n
.
BF3 Et2O
R1
R1
N
+
N
N
OMe
DCM
-78 ~ -45oC
R3
O
O
N
R2
O
O
R = H or OTBS, R1=Ar, Alkyl;
R2, R3 = Ts, Ar, Alkyl, or Bn
Bu-t
34 examples, dr up to 99:1
n = 0, 1
An efficient asymmetric approach to access functionalized pyrido and
pyrrolo[1,2-c][1,3]oxazin-1-ones has been developed through nucleophilic
addition-cyclization process of N,O-acetal with ynamides. A number of substituted
ynamides 8a-8o and 3-silyloxypyrrolidine or piperidine N, O-acetals 6a, 7 were
amenable to this transformation, and the desired products 9a-9o, 10a-10m were
obtained with excellent regioselectivities and outstanding diastereoselectivities.
Moreover, chiral ynamides 14a-14f could also experience this addition-cyclization
process to afford products 15a-15f in excellent yields.
Introduction
The development of a versatile approach to divergent skeleton construction is one of
the most important tasks in organic and pharmaceutical synthesis.1 As a prime
instance, nitrogen-containing heterocycles exist as subunits in numerous natural
products and many biologically active pharmaceuticals.2 In particular, functionalized
piperidine or pyrrolidine and their derived heterocyclic skeletons are very important
in synthetic and medicinal chemistry due to their contributions to numerous
biologically relevant alkaloids and pharmaceutical agents. Notably, they also serve as
useful building blocks.3 Typical examples include lythramine 1, hyperaspine 2,
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porantheridine 3, as well as geissolosimine 4 (Figure 1). The syntheses of these
natural products have attracted significant attention from many chemists due to their
intriguing structures and biological activities.4 For example, geissolosimine 4 showed
antiparasitic activities against Plasmodium falciparum and Leishmania don ovani, as
well as cytotoxic activity against the MRC-5 cell line.5 Although tremendous efforts
were devoted to the construction of the functionalized pyrido or
pyrrolo[1,2-c][1,3]oxazin-1-one scaffold,6 the more straightforward and efficient
approach is still in demand.
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H
H
N
H
N
N
HN
O
H
H
O
O
O
C3H7
N
H
H
Porantheridine 3
H
O
H
N
C5H9
N
O O
Lythramine 1
N
H
H
O
Hyperaspine 2
Geissolosimine 4
Figure 1. Natural products containing pyrido or pyrrolo [1,2-c][1,3]oxazine skeletons.
In the past decade, ynamides have undoubtedly become one of the most popular
synthons in modern organic synthesis, along with the discovery of more efficient
methods for accessing ynamides.7, 8 Many useful transformations from ynamides were
successfully realized through the transition-metal catalysis to generate important
acyclic and cyclic compounds, such as benzofurans,9 enamides,10 amidines,11
carbolines,12 oxazoles,13 quinolines,14 indoles,15 and pyridines.16 More recently,
several non-metal catalyzed conversions of ynamides were developed, such as
Brønsted acid catalyzed [3,3]-sigmatropic rearrangement17 and NBS-promoted
allyloxyl addition-Claisen rearrangement.18 On the basis of our efforts in the
transformation of N,O-acetals,19 we envisioned that the iminium ion could undergo
nucleophilic addition from ynamides and subsequent intramolecular cyclization to
give pyrido or pyrrolo[1,2-c][1,3]oxazin-1-ones (Figure 2). As a continuation of our
interest in developing diverse building blocks for natural products,20 herein we present
an efficient asymmetric approach from ynamides and N,O-acetals 6a, 7 through
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nucleophilic addition and subsequent intramolecular cyclization process.
5
6
7

R1
N
R2
R3

8
9
OTBS
OMe
OTBS
n
n
10
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Lewis acid
N
N
O
O
O
O
Bu-t
Bu-t
Nucleophilic addition
n = 0, 1
OTBS
R1
OTBS
R1
n
n
N
N
t-Bu
•
intramolecular
cyclization
R2
O
O
O
O
N
R3
N R3
R2
Figure 2. The strategy of addition-cyclization process.
Results and discussions
Our investigation started with the reaction of N,O-acetal 6a with ynamide 8a7c. When
8a was mixed with either 5 or 6a and stirred at room temperature for overnight, the
desired product 9a was not produced (Table 1, entries 1-2). When Sc(OTf)3 was used,
the mixture was treated at 0 oC for 2 h, the desired product 9a was obtained with high
diastereoselectivity (dr > 99:1) in 25% yield (Table 1, entry 3). To improve the
reaction yield, various Lewis acids were screened, and the results were summarized in
.
Table 1 (Table 1, entries 4-7). Delightfully, BF3 Et2O significantly increased the yield
of 9a up to 85% (Table 1, entry 7). Different stoichiometry of BF3•OEt2 was
examined, which resulted in significant drop of the yield of 9a (Table 1, entries 8-9).
When hemiacetal 5 was used in this reaction, the desired product 9a was obtained
with high diastereoselectivity (dr > 99:1), but only in 10% yield (Table 1, entry 10).
When 6b was used as substrate, the desired product 9a was obtained with 28% yield
and high diastereoselectivity (dr > 99:1) (Table 1, entry 11).
Table 1. Optimization of reaction conditions.
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OTBS
OTBS
Ts
5
6
7
8
Lewis acid
H
+
N
Ph
N
P
OR
DCM
N
Bn
8a
Bn
O
O
N
K-10,
MeOH
95%
5
R = H, P = Boc
R = Me, P = Boc
R = Me, P = Cbz
9
Ts
9a
6a
6b
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entrya Substrate
P
LA (equiv.)
--
Y% b trans:cisc
1
2
3d
4d
5d
6
5
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Cbz
0
--
6a
6a
6a
6a
6a
6a
6a
6a
5
--
0
--
Sc(OTf)3 (0.1)
In(OTf)3 (0.1)
Cu(OTf)2 (0.1)
TMSOTf (2.0)
25
15
20
46
85
68
38
10
28
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
.
7
BF3 Et2O (2.0)
.
8
BF3 Et2O (2.5)
.
9
BF3 Et2O (1.0)
.
10
11
BF3 Et2O (2.0)
.
6b
BF3 Et2O (2.0)
a The reactions were performed with BF3 Et2O (0.6 mmol), 5 or 6 (0.3 mmol) and 8a (0.36
mmol) in DCM (2 mL) at -78 ~ -45 oC for 2 h. b Isolated yield. c dr were determined by 1H
NMR of crude products. d Reaction temperature was 0 oC. K-10 = Montmorillonite K-10.
.
Next, we turned to investigate the scope and limitation of this nucleophilic addition
and intramolecular cyclization. Different TsN-substituted ynamides were surveyed
under the optimal conditions, as summarized in Scheme 1. In general, the reactions
with various TsN-substituted ynamides 8a-8e proceeded smoothly in moderate yields
and with excellent diastereoselectivities (9a-9e, 10a-10e). Various ynamides prepared
from different alkynes were also screened, and the results showed that most aryl and
alkyl substituted ynamides could smoothly lead to the desired products in moderate to
excellent yields and with excellent diastereoselectivities (9f-9j, 10f-10j). It is worth
mentioning that terminal ynamide could successfully provide the product 9o in 72%
yield in spite of low diastereoselectivity (75:25). Other N-substituted ynamides were
also screened, affording the desired products in moderate yields and with excellent
diastereoselectivities (9k-9n, 10k-10m). The stereochemistry of the products
pyrrolo[1,2-c][1,3]oxazin-1-ones 9a-9n were unambiguously assigned as trans- form
by X-ray crystallographic analysis of compound 9a (see Supporting Information).
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Scheme 1. The reactions with various substituted ynamides a-c
.
5
6
7
8
OTBS
R1
OTBS
n
R3
R2
n
.
BF3 Et2O
R1
N
+
N
N
OMe
DCM
9
R3
-78 ~ -45 oC
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O
O
N
O
O
R2
Bu-t
6
7
8a-o
9
10
(n = 0)
(n = 1)
(n = 0)
(n = 1)
OTBS
R1
OTBS
Ph
n
n
N
N
Ts
Ts
O
O
N
O
O
N
R2
Bn
2
1
9b
9c
9f
9g
9h
9i
n=0, R =Allyl, 83%, dr>99:1
n=0, R =4-BrC6H4, 64%, dr>99:1
1
2
n=0, R =4-ClC6H4, 96%, dr>99:1
n=0, R =n-C4H9, 67%, dr>99:1
1
2
n=0, R =4-MeC6H4, 91%, dr>99:1
9d
n=0, R =Ph, 54%, dr>99:1
1
2
n=0, R =4-MeOC6H4, 95%, dr>99:1
9e
n=0, R =Me, 86%, dr>99:1
1
2
9j
n=0, R =2-ClC6H4, 94%, dr>99:1
10a
10b
10c
10d
10e
n=1, R =Bn, 96%, dr>99:1
1
2
10f
10g
10h
10i
n=1, R =4-BrC6H4, 74%, dr>99:1
n=1, R =Allyl, 80%, dr>99:1
1
n=1, R =4-ClC6H4, 69%, dr>99:1
2
n=1, R =n-C4H9, 63%, dr>99:1
1
n=1, R =4-MeC6H4, 58%, dr>99:1
2
n=1, R =Ph, 87%, dr>99:1
1
n=1, R =4-MeOC6H4, 68%, dr>99:1
2
n=1, R =Me, 83%, dr>99:1
1
10j
n=1, R =2-ClC6H4, 51%, dr>99:1
OTBS
n
OTBS
Ph
Ph
N
N
COOEt
Ts
O
O
N
O
O
N
Bn
Bn
9k
n=0, 81%, dr>99:1
n=1, 61%, dr>99:1
9a
85% dr>99:1
OTBS
10k
n
OTBS
Ph
N
OTBS
N
n
O
Ph
N
R1
O
O
O
N
Bn
O
O
N
Bn
O
O
N
9l
n = 0, 50%, dr>99:1
O S
Cl
Ts
10l
n = 1, 41%, dr>99:1
O
1
9n
9o
9m
R =C6H13, 62% dr>99:1
R =H, 72% dr=75:25
n=0, 82%, dr>99:1
1
10m
n=1, 50%, dr>99:1
a
.
The reactions were performed with BF3 Et2O (0.6 mmol), N,O-acetal (0.3 mmol) and
ynamide (0.36 mmol) in dry DCM (2 mL) at -78 ~ -45 oC for 2 h. b Isolated yield. c dr were
determined by 1H NMR of crude products.
The structures of pyrido [1,2-c][1,3]oxazin-1-ones 10a-10m were also
unambiguously assigned based on the X-ray crystallographic analysis of
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compound 11 derived from ent-10a (see Scheme 2 and Supporting
Information).
7
8
Scheme 2. The transformation from ent-10a to 11.
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OH
HF.Py
95%
H
ent-10a
N
Ts
O
O
N
Bn
11
Then, several chiral ynamides7c were also explored. As summarized in Scheme
3, the desired products 15a-15f were successfully obtained from various
substituted chiral ynamides in moderatate yields, albeit with low
diastereoselectivities due to the lack of stereocontrol by OTBS group. To our
surprise, piperidine hemiacetal 13 did not react with ynamide 14a or 14e. The
stereochemistries of the major isomers 15a-15f were unambiguously assigned
based on the X-ray crystallographic analysis of compound 15c (see Supporting
Information).
Scheme 3. The reactions with different chiral ynamides a-c
.
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O
n
.
n
BF3 Et2O
R1
N
O
R1
OH+
N
N
N
O
DCM
-78 ~ -45oC
R3
7
8
9
O
O
O
O
Bu-t
R2
O
R2
R3
10
11
12
13
14
15
16
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12 (n = 0)
13 (n = 1)
15 (n = 0)
14a-f
16 (n = 1)
Cl
n
H
H
R
N
N
O
N
Bn
O
O
O
O
N
O
O
Bn
O
15a
16a
15b
n=0, R=Ph, 71%, dr=73:27
n=1, R=Ph, NR
n=0, R=4-MeC6H4, 92%, dr=71:29
15c
79%, dr=72:28
H
H
H
Ph
Ph
Ph
N
O
N
N
O
O
O
O
N
O
O
N
O
O
N
O
O
O
Ph
68%, dr=75:25
Ph
15d
15e
81%, dr=75:25
81%, dr= 74:26
15f
a
.
The reactions were performed with BF3 Et2O (0.6 mmol), hemiacetal (0.3 mmol) and
b
c
chiral ynamide (0.36 mmol) in DCM (2 mL) at -78 ~ -45 oC for 2 h. Isolated yield. dr
were determined by 1H NMR of crude products or column chromatography.
A possible mechanism for this nucleophilic addition-cyclization process was
illustrated in Figure 3. When N,O-acetal 7 reacted with ynamide 8a, imide
onium was first generated under Lewis acid conditions. Conformation a is more
stable than b due to allylic strain considerations where it is preferred to have the
alpha-H coplanar to the double bond.21 The axial OTBS stereocenter is
disposed for a Felkin type attack where ynamide 8a is preferred to attack from
axial orientation. Finally, the carbonyl of Boc group would attack the α position
of intermediate c to form the cyclization product 10a.22
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Nu
H
H
5
6
7
8
N
OTBS
N
TBS
O
O
O
O
TBS
OBu-t
a
OBu-t
b
N
OMe
Lewis acid
Nu
9
O
O
10
11
12
13
14
15
16
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22
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Boc
N
Boc
N
Bu-t
7
OTBS
H
Nu
OTBS
Ts
H
Nu
H
H
Nu
=
Ph
N
Bn
product
Nucleophilic addition process
isomer
OTBS
OTBS
Ph
Ph
N
N
Ts
H
•
O
O
10a
N
O
O
N Ts
Bn
c
Bn
intramolecular cyclization process
Figure 3. Proposed mechanism of the addition-cyclization.
Conclusion
In summary, we established a novel and efficient approach for highly regio-
and diastereoselective synthesis of functionalized pyrido and
pyrrolo[1,2-c][1,3]oxazin-1-ones 9a-9o, 10a-10m by treatment of N,O-acetals 6,
7 with ynamides 8a-8n. In addition, chiral ynamides 14a-14f were also
investigated. The reaction experienced a one-pot sequence of nucleophilic
addition and subsequent intramolecular cyclization process, providing an
efficient synthesis of chiral pyrido and pyrrolo[1,2-c][1,3]oxazin-1-ones in
moderate to excellent yields and with excellent diastereoselectivities.
Experimental Section
General Considerations THF was distilled from sodium/benzophenone. Reactions
were monitored by thin layer chromatography (TLC) on glass plates coated with silica
gel with fluorescent indicator. Flash chromatography was performed on silica gel
(300-400) with Petroleum/EtOAc or DCM/MeOH as eluent. Optical rotations were
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measured on a polarimeter with a sodium lamp. HRMS were measured on a
LTQ-Orbit. IR spectra were recorded using film on a Fourier Transform Infrared
Spectrometer. NMR spectra were recorded at 400 MHz or 600 MHz, and chemical
shifts are reported in δ (ppm) referenced to an internal TMS standard for 1H NMR and
CDCl3 (77.16 ppm) for 13C{1H} NMR.
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General Procedure for Synthesis of 6 and 7. To a solution of SM19a, 23 (8 mmol)
in dry THF (20 mL) was added solution of LiHBEt3 in THF (1 M, 1.1 eq, 8.8 mL) at
-78oC. The reaction mixture was stirred for 1 h at the same temperature, and the
reaction was quenched with water (5 mL) and warmed to room temperature. To the
mixture were added saturated aqueous NaHCO3 (20 mL) and 30% H2O2 solution (5
mL). After stirring for 1 h, the mixture was extracted with ethyl acetate (20 × 3), and
the combined organic layers were washed with brine. Dried, filtered, and concentrated,
the residue was purified by flash chromatography on silica gel (PE/EA = 10:1). The
product was dissolved in methol (15 ml) and Montmorillonite K 10 (400 mg) was
added to the solution. After stirring for 1 h, filtered, concentrated, the residue was
purified by flash chromatography on silica gel (PE/EA = 25:1).
tert-Butyl-(3S)-3-((tert-butyldimethylsilyl)oxy)-2-methoxypyrrolidine-1-carboxy
1
late (6a). Colorless oil (2.39 g, 90%). H NMR (400 MHz, CDCl3) δ 4.90-4.87 (m,
0.5H), 4.78-4.75 (m, 0.5H), 4.10 (d, J = 3.6 Hz, 1H), 3.63-3.55 (m, 0.5H), 3.51-3.44
(m, 0.5H), 3.40-3.32 (m, 4H), 2.12-2.00 (m, 1H), 1.79-1.70 (m, 1H), 1.48 (s, 9H),
0.92-0.84 (m, 9H), 0.12-0.06 (m, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 155.4
(156.0), 94.4, 80.1 (79.8), 75.2 (74.4), 55.6 (56.1), 44.1 (44.7), 31.0 (31.8), 28.5, 25.8
(26.0), 18.1, -4.7 (-4.6) ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for
C16H34NO4Si, 332.2246; found, 332.2247.
tert-Butyl-(3S)-3-((tert-butyldimethylsilyl)oxy)-2-methoxypiperidine-1-carboxyl
ate (7).Colorless oil (1.80 g, 65%). 1H NMR (400 MHz, CDCl3) δ 5.30-5.00 (m, 1H),
4.03-3.59 (m, 2H), 3.34-3.22 (m, 3H), 2.92-2.72 (m, 1H), 1.93-1.73 (m, 2H),
1.56-1.49 (m, 1H), 1.47 (s, 9H), 1.35-1.25 (m, 1H), 0.93-0.86 (m, 9H), 0.12-0.03 (m,
13
6H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 155.6, 85.7 (84.6), 79.8 (80.2), 71.3
(71.0), 66.8, 54.4 (55.2), 37.6 (36.8), 28.5 (27.8), 26.9, 25.8 (26.0), 18.1 (19.0), -4.8
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(-4.5), -5.0 (-4.6) ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C17H36NO4Si,
346.2403; found, 346.2403.
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General Procedure for Synthesis of 8a-8o and 14a-14f.7c To a mixture of an
amide (2 mmol), K3PO4 (4 mmol), CuSO4•5H2O (0.2mmol,) and 1,10-phenanthroline
(0.4 mmol,) in toluene at N2 atmosphere was added a solution 1-bromoalkyne (2.2
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o
mmol) in toluene. The reaction was stirred at 75 C for 24 h at N2 atmosphere. The
reaction mixture was cooled to room temperature and diluted with EtOAc and filtered
through Celite and the filtrate was concentrated in vacuo. The crude products were
purified by silica gel flash chromatography to afford the desired ynamide.
The data for new compounds of ynamides.
(R)-4-benzyl-3-(p-tolylethynyl)oxazolidin-2-one (14b). Pale yellow solid (495
1
mg, 85%). H NMR (400 MHz, CDCl3) δ 7.36-7.32 (m, 4H), 7.31-7.26 (m, 1H),
7.26-7.22 (m, 2H), 7.15-7.11 (m, 2H), 4.38-4.31 (m, 2H), 4.19-4.12 (m, 1H), 3.28 (dd,
J = 14.0, 3.6 Hz, 1H), 3.04-2.97 (m, 1H), 2.35 (s, 3H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 155.7, 138.6, 134.4, 131.8, 129.5, 129.2, 129.1, 127.6, 119.1, 77.3, 73.4,
67.5, 58.6, 38.1, 21.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C19H18NO2,
292.1327; found, 292.1330.
(R)-4-benzyl-3-((4-chlorophenyl)ethynyl)oxazolidin-2-one (14c). Pale yellow
solid (511 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 7.39-7.32 (m, 4H), 7.32-7.27 (m,
3H), 7.26-7.21 (m, 2H), 4.42-4.32 (m, 2H), 4.22-4.14 (m, 1H), 3.27 (dd, J = 14.0, 3.6
13
Hz, 1H), 3.04-2.97 (m, 1H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 155.5, 134.4,
134.2, 132.9, 129.5, 129.2, 128.8, 127.7, 120.8, 79.0, 72.4, 67.7, 58.6, 38.2 ppm;
HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C18H15ClNO2, 312.0780; found,
312.0785.
General Procedure for Synthesis of 9 and 10. To a solution of 6a (0.3 mmol)
or 7 (0.3 mmol) and 87c (0.36 mmol) in dry DCM (2 mL) was added dropwise
.
BF3 Et2O (76 μL, 0.6 mmol) at -78oC. The reaction was allowed to warm to -45 oC
slowly and stirred for 2 h at -45 oC. Saturated aqueous NaHCO3 (2 mL) was added to
quench the reaction. The mixture was extracted with DCM (5 × 3) and the combined
organic layers were washed with brine. Dried, filtered, and concentrated, the residue
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was purified by flash chromatography on silica gel (PE/EA = 5:1) to give 9 or 10.
N-benzyl-N-((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,6,7-
7
8
tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamide
(9a).
9
White solid (154 mg, 85%), mp 140-142 oC. [α]D +89.1 (c 1.78, CHCl3); IR (film):
νmax 3030, 2952, 2927, 2854, 1743, 1682, 1649, 1354, 1164, 1012, 773, 675 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.88-7.64 (m, 2H), 7.33-7.29 (m, 2H), 7.26-7.17 (m, 4H),
7.15-7.07 (m, 2H), 7.06-6.89 (m, 2H), 6.88-6.72 (m, 2H), 4.28-4.18 (m, 1H),
4.12-3.94 (m, 3H), 3.93-3.83 (m, 1H), 3.50-3.42 (m, 1H), 2.43 (s, 3H), 2.11-1.97 (m,
1H), 1.70-1.60 (m, 1H), 0.66 (s, 9H), -0.22 (s, 3H), -0.60 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 148.6, 144.3, 138.0, 135.7, 133.8, 129.7, 129.4, 128.7, 128.3,
128.1, 128.0, 127.9, 75.3, 65.1, 51.8, 44.1, 32.7, 25.7, 21.7, 17.6, -4.5, -5.8 ppm;
HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C33H41N2O5SSi, 605.2500; found,
605.2504.
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N-allyl-N-((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,6,7-tet
rahydro-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamide (9b). White
o
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solid (138 mg, 83%), mp 129-130 C. [α]D +101 (c 0.815, CHCl3); IR (film): νmax
3066, 2952, 2928, 2855, 1741, 1681, 1355, 1165, 868, 746, 677 cm-1; H NMR (400
1
MHz, CDCl3) δ 7.82-7.72 (m, 2H), 7.44-7.35 (m, 4H), 7.34-7.28 (m, 3H), 5.38-5.21
(m, 1H), 5.03-4.93 (m, 2H), 4.45 (d, J = 6.4 Hz, 1H), 4.14 (dd, J = 12.8, 6.0 Hz, 1H),
3.93-3.85 (m, 1H), 3.63-3.56 (m, 1H), 3.55-3.47 (m, 1H), 3.45-3.36 (m, 1H), 2.42 (m,
3H), 2.19-2.09 (m, 1H), 1.77-1.67 (m, 1H), 0.70 (s, 9H), -0.16 (s, 3H), -0.54 (s, 3H)
ppm; C{1H} NMR (100 MHz, CDCl3) δ 148.5, 144.3, 138.7, 136.0, 132.1, 131.6,
13
129.7, 129.6, 128.6, 128.5, 128.2, 119.8, 75.4, 65.0, 51.3, 44.1, 32.8, 25.8, 21.7, 17.7,
-4.4, -5.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C29H39N2O5SSi,
555.2344; found, 555.2346.
N-butyl-N-((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,6,7-te
trahydro-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamide
(9c).
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White solid (115 mg, 67%), mp 133-135 oC. [α]D +116 (c 2.23, CHCl3); IR (film):
νmax 3057, 2959, 2929, 2856, 1738, 1681, 1355, 1167, 837, 775, 678 cm-1; H NMR
1
(400 MHz, CDCl3) δ 7.81-7.73 (m, 2H), 7.48-7.43 (m, 2H), 7.39-7.33 (m, 2H),
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7.33-7.27 (m, 3H), 4.48 (d, J = 6.4 Hz, 1H), 4.19-4.12 (m, 1H), 3.95-3.87 (m, 1H),
3.55-3.47 (m, 1H), 2.96-2.87 (m, 1H), 2.85-2.74 (m, 1H), 2.40 (s, 3H), 2.20-2.10 (m,
1H), 1.77-1.68 (m, 1H), 1.18-1.05 (m, 2H), 0.97-0.82 (m, 2H), 0.70 (s, 9H), 0.67-0.61
(m, 3H), -0.17 (s, 3H), -0.55 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 148.6,
144.1, 138.7, 136.0, 132.2, 129.6, 129.4, 128.7, 128.5, 128.2, 116.1, 75.5, 65.2, 48.1,
44.1, 32.8, 29.7, 25.8, 21.7, 19.7, 17.7, 13.6, -4.4, -5.8 ppm; HRMS (ESI-Orbitrap)
m/z: [M + H]+ calcd for C30H43N2O5SSi, 571.2656; found, 571.2657.
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N-((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,6,7-tetrahydro
-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-4-methyl-N-phenylbenzenesulfonamide
(9d).
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White solid (96 mg, 54%), mp 158-160 oC. [α]D +44.0 (c 1.32, CHCl3); IR (film):
1
νmax 3063, 2953, 2928, 2856, 1747, 1682, 1361, 1156, 838, 772, 696 cm-1; H NMR
(400 MHz, CDCl3) δ 7.56-7.52 (m, 2H), 7.35-7.27 (m, 5H), 7.21-7.17 (m, 2H),
7.16-7.12 (m, 1H), 7.08-7.02 (m, 2H), 6.70-6.63 (m, 2H), 4.33 (d, J = 6.4 Hz, 1H),
4.16 (dd, J = 6.4, 13.2 Hz, 1H), 3.93-3.85 (m, 1H), 3.55-3.47 (m, 1H), 2.37 (s, 3H),
2.22-2.10 (m, 1H), 1.76-1.66 (m, 1H), 0.65 (s, 9H), -0.18 (s, 3H), -0.58 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 148.5, 144.2, 140.6, 138.2, 135.5, 132.0, 129.6,
129.3, 128.8, 128.6, 128.5, 128.3, 128.1, 115.4, 75.2, 65.1, 44.1, 32.7, 25.7, 21.7, 17.7,
-4.4, -5.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C32H39N2O5SSi,
591.2343; found, 591.2347.
N-((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,6,7-tetrahydro
-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-N,4-dimethylbenzenesulfonamide (9e). White
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solid (136 mg, 86%), mp 167-169 oC. [α]D +98.7 (c 0.905, CHCl3); IR (film): νmax
1
3055, 2953, 2928, 2856, 1743, 1682, 1355, 1159, 837, 772, 678 cm-1; H NMR (400
MHz, CDCl3) δ 7.70-7.65 (m, 2H), 7.40-7.36 (m, 4H), 7.36-7.30 (m, 2H), 7.28 (s, 1H),
4.47 (d, J = 6.4 Hz, 1H), 4.13 (dd, J = 13.2, 6.4 Hz, 1H), 3.94-3.86 (m, 1H), 3.55-3.47
(m, 1H), 2.70 (s, 3H), 2.41 (s, 3H), 2.18-2.08 (m, 1H), 1.78-1.68 (m, 1H), 0.71 (s, 9H),
13
-0.16 (s, 3H), -0.53 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 148.6, 144.2,
140.7, 135.2, 132.3, 129.7, 129.2, 128.6, 128.5, 128.3, 114.6, 75.4, 65.1, 44.1, 35.8,
32.7, 25.8, 21.7, 17.7, -4.4, -5.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for
C27H37N2O5SSi, 529.2187; found: 529.2186.
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N-Benzyl-N-((4aS,5R)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,7,8-
tetrahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamide (10a).
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Foam solid (178 mg, 96%). [α]D -56.3 (c 1.38, CHCl3); IR (film): νmax 3030, 2951,
9
2927, 2856, 1731, 1682, 836, 773 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.95-7.70 (m,
2H), 7.35-7.27 (m, 2H), 7.25-7.16 (m, 6H), 7.15-6.95 (m, 3H), 6.75 (s, 1H), 4.25-4.16
(m, 2H), 4.05-3.80 (m, 2H), 3.76-3.66 (m, 1H), 2.75-2.65 (m, 1H), 2.43 (s, 3H),
2.11-2.06 (m, 1H), 1.78-1.65 (m, 2H), 1.49-1.40 (m, 1H), 0.53 (s, 9H), -0.13 (s, 3H),
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13
-0.23 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 150.8, 144.3, 135.8, 134.1,
133.6, 129.7, 129.2, 128.7, 128.3, 127.9, 127.5, 72.4, 65.2, 52.1, 46.0, 35.6, 25.6, 23.1,
21.8, 17.8, -4.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C34H43N2O5SSi,
619.2656; found, 619.2659.
N-Allyl-N-((4aS,5R)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,7,8-te
trahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamide (10b).
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Foam solid (136 mg, 80%). [α]D +27.0 (c 1.91, CHCl3); IR (film): νmax 3033, 2949,
2927, 2855, 1735, 1731, 1219, 772 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.88-7.76 (m,
2H), 7.62-7.57 (m, 2H), 7.38-7.34 (m, 2H), 7.34-7.27 (m, 3H), 5.05-4.85 (m, 2H),
4.29-4.20 (m, 1H), 4.10 (d, J = 9.2 Hz, 1H), 3.83-3.73 (m, 1H), 3.70-3.50 (m, 2H),
2.84-2.75 (m, 1H), 2.43 (s, 3H), 2.17-2.09 (m, 1H), 1.85-1.69 (m, 2H), 1.62-1.59 (m,
1H), 1.58-1.46 (m, 1H), 0.60 (s, 9H), -0.06 (s, 3H), -0.14 (s, 3H) ppm; 13C{1H} NMR
(150 MHz, CDCl3) δ 149.9, 143.3, 135.1, 133.3, 130.4, 128.7, 127.7, 127.6, 127.2,
126.8, 118.9, 71.6, 64.2, 50.4, 45.2, 34.8, 24.7, 22.2, 20.8, 16.8, -5.2, -5.3 ppm;
HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C30H41N2O5SSi, 569.2500; found,
569.2504.
N-Butyl-N-((4aS,5R)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,7,8-t
etrahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamide (10c).
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Foam solid (110 mg, 63%). [α]D +39.5 (c 1.17, CHCl3); IR (film): νmax 3055, 2955,
1
2928, 2875, 1738, 1731, 1166, 837, 766 cm-1; H NMR (400 MHz, CDCl3) δ
7.86-7.79 (m, 2H), 7.67-7.63 (m, 2H), 7.38-7.30 (m, 4H), 7.28-7.24 (m, 1H), 4.27 (dd,
J = 11.6, 2.4 Hz, 1H), 4.12 (d, J = 9.2 Hz, 1H), 3.86-3.79 (m, 1H), 3.02-2.90 (m, 2H),
2.86-2.77 (m, 1H), 2.42 (s, 3H), 2.20-2.10 (m, 1H), 1.89-1.70 (m, 2H), 1.60-1.48 (m,
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1H), 1.20-0.80 (m, 4H), 0.66-0.58 (m, 12H), -0.05 (s, 3H), -0.12 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 151.1, 144.1, 138.9, 136.0, 134.3, 129.7, 128.7, 128.7,
128.2, 127.8, 117.6, 72.5, 65.3, 48.5, 46.2, 35.8, 25.7, 23.2, 21.7, 19.8, 17.8, 13.7, -4.3
ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C31H45N2O5SSi, 585.2813; found,
585.2816.
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N-((4aS,5R)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,7,8-tetrahydro
-1H,6H-pyrido[1,2-c][1,3]oxazin-3-yl)-4-methyl-N-phenylbenzenesulfonamide (10d).
Foam solid (158 mg, 87%). [α]D24 -6.35 (c 1.28, CHCl3); IR (film): νmax 2993, 29511,
2927, 2856, 1738, 1731, 1361, 1159, 836, 756, 694 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.61-7.56 (m, 4H), 7.38-7.31 (m, 2H), 7.30-7.25 (m, 1H), 7.23-7.18 (m, 2H),
7.19-7.13 (m, 1H), 7.12-7.05 (m, 2H), 6.94-6.83 (m, 2H), 4.30-4.24 (m, 1H), 4.00 (d,
J = 9.6 Hz, 1H), 3.84-3.76 (m, 1H), 2.84-2.74 (m, 1H), 2.38 (s, 3H), 2.15-2.08 (m,
1H), 1.87-1.69 (m, 2H), 1.57-1.46 (m, 1H), 0.58 (s, 9H), -0.13 (s, 3H), -0.34 (s, 3H)
13
ppm; C{1H} NMR (100 MHz, CDCl3) δ 150.9, 144.3, 140.7, 138.8, 135.3, 134.0,
129.3, 129.1, 129.0, 129.0, 128.3, 128.1, 127.9, 127.6, 116.9, 72.2, 65.2, 46.3, 35.7,
25.6, 23.2, 21.7, 17.8, -4.5 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for
C33H41N2O5SSi, 605.2500; found, 605.2502.
N-((4aS,5R)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,7,8-tetrahydro
-1H,6H-pyrido[1,2-c][1,3]oxazin-3-yl)-N,4-dimethylbenzenesulfonamide (10e). Foam
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solid (135 mg, 83%). [α]D +3.2 (c 1.62, CHCl3); IR (film): νmax 2950, 2928, 2856,
1738, 1731,1361, 1160, 837, 768, 672 cm-1; 1H NMR (400 MHz, CDCl3) δ 7,77-7.72
(m, 2H), 7.60-7.56 (m, 2H), 7.37-7.23 (m, 5H), 4.29-4.22 (m, 1H), 4.10 (d, J = 9.2 Hz,
1H), 3.80-3.73 (m, 1H), 2.85-2.76 (m, 4H), 2.42 (s, 3H), 2.17-2.09 (m, 1H), 1.86-1.69
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(m, 2H), 1.60-1.49 (m, 1H), 0.62 (s, 9H), -0.07 (s, 3H), -0.17 (s, 3H) ppm; C{1H}
NMR (100 MHz, CDCl3) δ 151.0, 144.2, 140.9, 135.3, 134.0, 129.7, 128.5, 128.3,
127.8, 115.5, 72.4, 64.8, 46.3, 35.8, 35.8, 25.7, 23.2, 21.7, 17.9, -4.3, -4.4 ppm;
HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C28H39N2O5SSi, 543.2344; found,
543.2346.
N-benzyl-N-((4aR,5S)-4-(4-bromophenyl)-5-((tert-butyldimethylsilyl)oxy)-1-ox
o-4a,5,6,7-tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamid
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e (9f). White solid (131 mg, 64%), mp 123-125 oC. [α]D +69.8 (c 1.06, CHCl3); IR
(film): νmax 2955, 2929, 2856, 1740, 1654, 1354, 1253, 1164, 837, 749 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.88-7.68 (m, 2H), 7.38-7.28 (m, 5H), 7.25-7.07 (m, 3H),
6.98-6.74 (m, 3H), 4.20-4.12 (m, 2H), 4.06-3.79 (m, 3H), 3.52-3.44 (m, 1H), 2.45 (s,
3H), 2.17-2.02 (m, 1H), 1.72-1.63 (m, 1H), 0.65 (s, 9H), -0.19 (s, 3H), -0.56 (s, 3H)
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ppm; C{1H} NMR (100 MHz, CDCl3) δ 148.4, 144.6, 138.1, 135.4, 133.6, 131.2,
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131.1, 130.7, 129.8, 129.4, 128.8, 128.4, 128.2, 122.1, 116.2, 75.3, 64.5, 51.8, 43.9,
32.5, 25.6, 21.8, 17.6, -4.3, -5.8 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for
C33H40BrN2O5SSi, 683.1605; found, 683.1602.
N-benzyl-N-((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-4-(4-chlorophenyl)-1-ox
o-4a,5,6,7-tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamid
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e (9g). White solid (184 mg, 96%), mp 134-136 oC. [α]D +72.4 (c 1.76, CHCl3); IR
(film): νmax 3030, 2952, 2928, 2856, 1747, 1682, 1355, 1256, 1164, 837, 776 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.90-7.68 (m, 2H), 7.38-7.32 (m, 2H), 7.28-7.19 (m, 2H),
7.19-7.08 (m, 4H), 7.00-6.70 (m, 3H), 4.25-4.11 (m, 2H), 4.08-3.88 (m, 2H),
3.88-3.80 (m, 1H), 3.52-3.44 (m, 1H), 2.45 (s, 3H), 2.16-2.03 (m, 1H), 1.72-1.65 (m,
1H), 0.66 (s, 9H), -0.18 (s, 3H), -0.56 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3)
δ 148.4, 144.5, 138.1, 135.4, 133.8, 133.6, 130.8, 130.2, 129.8, 129.5, 128.7, 128.4,
128.2, 116.1, 77.4, 75.2, 64.6, 51.8, 43.9, 32.5, 25.6, 21.7, 17.6, -4.3, -5.8 ppm;
HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C33H40ClN2O5SSi, 639.2110; found,
639.2110.
N-benzyl-N-((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-(p-tolyl)-4a,5,6,
7-tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamide (9h).
White solid (169 mg, 91%), mp 138-140 oC. [α]D +81.4 (c 1.02, CHCl3); IR (film):
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νmax 3030, 2952, 2928, 2855, 1743, 1649, 1164, 837, 777, 666 cm-1; H NMR (400
1
MHz, CDCl3) δ 7.87-7.66 (m, 2H), 7.33-7.27 (m, 2H), 7.22-7.06 (m, 3H), 7.06-6.98
(m, 3H), 6.92-6.70 (m, 3H), 4.23-4.13 (m, 1H), 4.10-3.93 (m, 3H), 3.89-3.80 (m, 1H),
3.48-3.40 (m, 1H), 2.43 (s, 3H), 2.34 (s, 3H), 2.10-1.95 (m, 1H), 1.69-1.63 (m, 1H),
0.66 (s, 9H), -0.22 (s, 3H), -0.58 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ
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148.7, 144.3, 137.7, 135.9, 134.0, 129.7, 129.2, 128.9, 128.7, 128.3, 128.0, 75.3, 65.1,
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51.8, 44.1, 32.8, 25.7, 21.8, 21.3, 17.7, -4.4, -5.8 ppm; HRMS (ESI-Orbitrap) m/z: [M
+ H]+ calcd for C34H43N2O5SSi, 619.2656; found, 619.2658.
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N-benzyl-N-((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-4-(4-methoxyphenyl)-1-o
xo-4a,5,6,7-tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonami
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de (9i). White solid (181 mg, 95%), mp 64-66 oC. [α]D +73.7 (c 1.98, CHCl3); IR
(film): νmax 3032, 2953, 2929, 2855, 1740, 1609, 1164, 836, 779, 666 cm-1; H NMR
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(400 MHz, CDCl3) δ 7.86-7.73 (m, 2H), 7.35-7.29 (m, 3H), 7.24-7.05 (m, 3H),
6.90-6.70 (m, 5H), 4.21-4.14 (m, 1H), 4.08-3.99 (m, 3H), 3.90-3.83 (m, 1H), 3.82 (s,
3H), 3.49-3.40 (m, 1H), 2.44 (s, 3H), 2.10-1.98 (m, 1H), 1.66-1.60 (m, 1H), 0.68 (s,
9H), -0.20 (s, 3H), -0.54 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 159.4,
13
148.7, 144.3, 137.8, 135.8, 133.9, 130.6, 129.7, 129.3, 128.7, 128.3, 128.0, 124.1,
113.7, 75.4, 65.1, 55.4, 51.8, 44.1, 32.8, 25.7, 21.7, 17.7, -4.4, -5.7 ppm; HRMS
(ESI-Orbitrap) m/z: [M + H]+ calcd for C34H43N2O6SSi, 635.2606; found, 635.2604.
N-benzyl-N-((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-4-(2-chlorophenyl)-1-ox
o-4a,5,6,7-tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamid
e (9j). Foam solid (180 mg, 94%). [α]D24 +48.9 (c 1.59, CHCl3); IR (film): νmax 3066,
3032, 2953, 2925, 2849, 1738, 1689, 1649, 1361, 1219, 838, 771, 673 cm-1; 1H NMR
(400 MHz, CDCl3, rotamers) δ 7.75-7.70 (m, 1.78H), 7.57-7.53 (m, 0.22H), 7.38-7.23
(m, 5H), 7.22-7.15 (m, 2H), 7.11-7.05 (m, 2H), 6.90-6.84 (m, 2H), 4.66-4.62 (m,
0.88H), 4.33-4.31 (m, 0.12H), 4.18-4.04 (m, 2H), 4.02-3.93 (m, 1H), 3.85-3.76 (m,
1H), 3.57-3.49 (m, 1H), 2.41 (s, 2.70H), 2.38 (s, 0.30H), 2.15-2.02 (m, 1H), 1.76-1.66
(m, 1H), 0.67 (s, 8.09H), 0.63 (s, 0.91H), -0.18 (s, 3H), -0.49 (s, 0.22H), -0.55 (s,
2.78H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 148.6, 144.3, 136.0, 135.1, 134.4,
13
132.4, 131.3, 129.8, 129.7, 129.6, 128.8, 128.7, 128.4, 128.3, 127.9, 127.1, 74.8, 63.0,
52.6, 43.9, 32.6, 25.7, 21.7, 17.6, -4.2, -5.6 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+
calcd for C33H40ClN2O5SSi, 639.2110; found, 639.2111.
N-benzyl-N-((4aS,5R)-4-(4-bromophenyl)-5-((tert-butyldimethylsilyl)oxy)-1-ox
o-4a,5,7,8-tetrahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfona
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mide (10f). Foam solid (155 mg, 74%). [α]D +38.1 (c 1.94, CHCl3); IR (film): νmax
3029, 2951, 2928, 2855, 1731, 1682, 1361, 1258, 1164, 837, 753, 676 cm-1; 1H NMR
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(400 MHz, CDCl3) δ 8.00-7.70 (m, 2H), 7.36-7.28 (m, 5H), 7.20-6.96 (m, 6H),
4.32-4.20 (m, 2H), 3.90-3.60 (m, 3H), 2.76-2.66 (m, 1H), 2.45 (s, 3H), 2.12-2.05 (m,
1H), 1.79-1.68 (m, 2H), 1.46-1.38 (m, 1H), 0.54 (s, 9H), -0.07--0.20 (m, 6H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 150.5, 144.5, 135.5, 133.3, 131.0, 130.4, 129.8,
129.4, 128.8, 128.3, 121.5, 72.5, 65.1, 52.0, 46.1, 35.7, 25.5, 23.2, 21.8, 17.7, -4.2
ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C34H42BrN2O5SSi, 697.1762;
found, 697.1766.
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N-benzyl-N-((4aS,5R)-5-((tert-butyldimethylsilyl)oxy)-4-(4-chlorophenyl)-1-ox
o-4a,5,7,8-tetrahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfona
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mide (10g). Foam solid (135 mg, 69%). [α]D +46.9 (c 1.48, CHCl3); IR (film): νmax
3032, 2952, 2928, 2857, 1747, 1689, 1649, 1219, 772, 674 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.95-7.67 (m, 2H), 7.37-7.30 (m, 2H), 7.20-7.96 (m, 8H), 6.80 (s, 1H),
4.31-4.20 (m, 2H), 3.98-3.62 (m, 3H), 2.75-2.66 (m, 1H), 2.45 (s, 3H), 2.13-2.05 (m,
1H), 1.82-1.66 (m, 2H), 1.48-1.39 (m, 1H), 0.54 (s, 9H), -0.0--0.36 (m, 6H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 150.6, 144.5, 135.5, 133.3, 132.8, 130.0, 129.8,
129.4, 128.7, 128.3, 128.1, 128.0, 72.5, 65.1, 52.0, 46.1, 35.7, 25.5, 23.2, 21.8, 17.7,
-4.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C34H42ClN2O5SSi, 653.2267;
found, 653.2268.
N-benzyl-N-((4aS,5R)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-(p-tolyl)-4a,5,7,
8-tetrahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamide
(10h). Foam solid (110 mg, 58%). [α]D24 +39.6 (c 1.86, CHCl3); IR (film): νmax 3029,
2952, 2927, 2855, 1731, 1682, 1649, 1219, 1163, 772, 686 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.95-7.65 (m, 2H), 7.35-7.24 (m, 2H), 7.19-7.10 (m, 4H), 7.08-6.98 (m, 4H),
6.78 (s, 1H), 4.30-4.15 (m, 2H), 4.12-3.93 (m, 1H), 3.90-3.81 (m, 1H), 3.75-3.64 (m,
1H), 2.75-2.65 (m, 1H), 2.43 (s, 3H), 2.32 (s, 3H), 2.11-2.03 (m, 1H), 1.82-1.64 (m,
2H), 1.49-1.39 (m, 1H), 0.54 (s, 9H), -0.12 (s, 3H), -0.24 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 150.9, 144.2, 137.2, 136.0, 131.1, 129.7, 129.2, 128.7, 128.6,
128.5, 128.2, 127.9, 72.3, 65.2, 52.1, 46.0, 35.7, 25.6, 23.1, 21.8, 21.2, 17.7, -4.4, -4.4
ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C35H45N2O5SSi, 633.2813; found,
633.2815.
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N-benzyl-N-((4aS,5R)-5-((tert-butyldimethylsilyl)oxy)-4-(4-methoxyphenyl)-1-o
xo-4a,5,7,8-tetrahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfon
amide (10i). Foam solid (132 mg, 68%). [α]D24 +41.9 (c 1.62, CHCl3); IR (film): νmax
3033, 2952, 2927, 2855, 1731, 1682, 1649, 1219, 1163, 772, 686 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.94-7.73 (m, 2H), 7.34-7.28 (m, 2H), 7.24-7.18 (m, 3H), 7.16-6.96
(m, 3H), 6.82-6.72 (m, 3H), 4.30-4.16 (m, 2H), 4.15-3.90 (m, 1H), 3.88-3.78 (m, 4H),
3.76-3.62 (m, 1H), 2.75-2.64 (m, 1H), 2.44 (s, 3H), 2.11-2.03 (m, 1H), 1.83-1.64 (m,
2H), 1.50-1.36 (m, 1H), 0.56 (s, 9H), -0.11 (s, 3H), -0.22 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 159.1, 151.0, 144.3, 135.9, 129.9, 129.7, 129.2, 128.8, 128.7,
128.2, 128.1, 128.0, 127.9, 127.3, 126.5, 113.4, 72.3, 65.2, 55.5, 52.2, 46.0, 35.7, 25.6,
23.2, 21.8, 17.8, -4.4, -4.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for
C35H45N2O6SSi, 649.2762; found, 649.2763.
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N-benzyl-N-((4aS,5R)-5-((tert-butyldimethylsilyl)oxy)-4-(2-chlorophenyl)-1-ox
o-4a,5,7,8-tetrahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfona
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mide (10j). Foam solid (100 mg, 51%). [α]D +87.9 (c 1.38, CHCl3); IR (film): νmax
3055, 2962, 2934, 2879, 1682, 1649, 1397, 1213, 1065, 768, 706 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.84-7.78 (m, 2H), 7.34-7.29 (m, 2H), 7.28-7.21 (m, 2H), 7.20-7.13
(m, 2H), 7.12-7.08 (m, 1H), 7.09-7.00 (m, 2H), 6.86-6.78 (m, 2H), 4.26-4.11 (m, 3H),
4.05-3.95 (m, 1H), 3.90-3.81 (m, 1H), 2.80-2.69 (m, 1H), 2.43 (s, 3H), 2.15-2.06 (m,
1H), 1.83-1.72 (m, 1H), 1.72-1.64 (m, 1H), 1.46-1.34 (m, 1H), 0.62 (s, 9H), -0.04 (s,
13
3H), -0.12 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 150.5, 144.4, 140.1,
135.6, 133.9, 133.0, 132.8, 129.8, 129.2, 129.0, 128.7, 128.4, 128.0, 126.6, 117.6,
72.7, 63.7, 52.1, 46.0, 35.4, 25.9, 23.0, 21.8, 18.0, -3.3, -3.7 ppm; HRMS
(ESI-Orbitrap) m/z: [M + H]+ calcd for C34H42ClN2O5SSi, 653.2267; found, 653.2269.
Ethylbenzyl((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,6,7-t
etrahydro-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)carbamate (9k). White solid (127 mg,
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81%), mp 83-84 oC. [α]D +85.1 (c 1.33, CHCl3); IR (film): νmax 3033, 2953, 2929,
2855, 1742, 1649, 1377, 1219, 772, 699 cm-1; 1H NMR (400 MHz, CDCl3, rotamers)
δ 7.37-7.27 (m, 3H), 7.22-6.98 (m, 6H), 6.68-6.54 (m, 1H), 4.55-4.39 (m, 1H),
4.38-4.22 (m, 2H), 4.10-3.98 (m, 1H), 3.97-3.83 (m, 2H), 3.74-3.61 (m, 1H),
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3.56-3.40 (m, 1H), 2.18-1.95 (m, 1H), 1.94-1.65 (m, 1H), 1.74-1.65 (m, 1H),
1.43-1.32 (m, 1H), 1.30-1.15 (m, 1H), 1.10-0.98 (m, 1H), 0.68 (s, 9H), -0.19 (s, 3H),
-0.58 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3, rotamers) δ 155.7, 149.1, 140.9,
136.1, 132.4, 129.8, 128.7, 128.4, 128.2, 127.8, 127.6, 111.1, 75.5, 64.2 (65.2), 62.8
(62.4), 51.2, 43.9 (44.2), 32.6 (32.8), 25.8, 17.7, 14.8 (14.4), -4.4, -5.8 ppm; HRMS
(ESI-Orbitrap) m/z: [M + H]+ calcd for C29H39N2O5Si, 523.2623; found, 523.2621.
Ethylbenzyl((4aS,5R)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,7,8-t
etrahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-3-yl)carbamate (10k). Foam solid (98 mg,
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61%). [α]D +51.7 (c 1.62, CHCl3); IR (film): νmax 3030, 2951, 2929, 2856, 1731,
1
1682, 1649, 1252, 1108, 775, 697 cm-1; H NMR (400 MHz, CDCl3, rotamers) δ
7.44-7.30 (m, 1H), 7.25-7.17 (m, 3H), 7.16-7.10 (m, 4H), 6.95 (s, 1H), 4.75-4.16 (m,
4H), 4.02-3.88 (m, 2H), 3.76-3.64 (m, 1H), 2.84-2.66 (m, 1H), 2.10 (d, J = 10.0 Hz,
1H), 1.88-1.68 (m, 2H), 1.52-1.32 (m, 3H), 1.06-0.96 (m, 1H), 0.64-0.50 (m, 9H),
-0.13 (s, 3H), -0.20--0.37 (m, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3, rotamers) δ
156.0, 151.2, 140.3 (141.2), 135.5 (136.7), 134.4 (134.8), 128.8, 128.4, 128.2, 127.9,
127.5, 113.6, 72.5, 64.3 (64.8), 62.8 (62.6), 51.5 (52.0), 46.0 (46.3), 35.7, 25.6, 23.2,
17.8, 14.8 (14.3), -4.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for
C30H41N2O5Si, 537.2779; found, 537.2788.
(4aR,5S)-5-((tert-Butyldimethylsilyl)oxy)-3-(2-oxooxazolidin-3-yl)-4-phenyl-4a,
5,6,7-tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazin-1-one (9l). White solid (65 mg, 50%),
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mp 89-91 oC. [α]D +83.0 (c 1.51, CHCl3); IR (film): νmax 3033, 2952, 2927, 2855,
1736, 1649, 1253, 1126, 775, 701 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.35-7.28 (m,
3H), 7.27-7.23 (m, 2H), 4.46 (d, J = 6.8 Hz, 1H), 4.29-4.22 (m, 1H), 4.22-4.14 (m,
1H), 4.14-4.08 (m, 1H), 3.93-3.85 (m, 1H), 3.68-3.61 (m, 1H), 3.58-3.48 (m, 2H),
2.19-2.09 (m, 1H), 1.77-1.68 (m, 1H), 0.68 (s, 9H), -0.18 (s, 3H), -0.57 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 155.6, 148.4, 136.9, 132.0, 128.8, 128.6, 128.5,
113.5, 75.3, 64.8, 62.7, 44.6, 44.1, 32.6, 25.7, 17.7, -4.4, -5.8 ppm; HRMS
(ESI-Orbitrap) m/z: [M + H]+ calcd for C22H31N2O5Si, 431.1997; found: 431.1995.
(4aS,5R)-5-((tert-Butyldimethylsilyl)oxy)-3-(2-oxooxazolidin-3-yl)-4-phenyl-4a,
5,7,8-tetrahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-1-one (10l). Foam solid (55 mg,
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41%). [α]D +61.0 (c 1.11, CHCl3); IR (film): νmax 2952, 2928, 2856, 1730, 1647,
1398, 1219, 1162, 1104, 836, 771, 700 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.41-7.31
(m, 2H), 7.35-7.29 (m, 2H), 7.26-7.22 (m, 1H), 4.39-4.22 (m, 3H), 4.12 (d, J = 9.2 Hz,
1H), 3.86-3.74 (m, 2H), 3.53-3.46 (m, 1H), 2.86-2.78 (m, 1H), 2.18-2.10 (m, 1H),
1.84-1.72 (m, 2H), 1.60-1.48 (m, 1H), 0.59 (s, 9H), -0.08 (s, 3H), -0.18 (s, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 156.2, 150.7, 136.9, 134.1, 128.5, 128.0, 127.9,
115.2, 72.8, 64.8, 62.9, 46.3, 44.4, 35.7, 25.7, 23.3, 17.8, -4.2, -4.4 ppm; HRMS
(ESI-Orbitrap) m/z: [M + H]+ calcd for C23H33N2O5Si, 445.2153; found, 445.2156.
N-benzyl-N-((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,6,7-
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tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-4-chlorobenzenesulfonamide
(9m).
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Foam solid (154 mg, 82%). [α]D +85.2 (c 1.14, CHCl3); IR (film): νmax 3030, 2952,
2928, 2855, 1743, 1682, 1649, 1361, 1166, 772, 698 cm-1; H NMR (400 MHz,
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CDCl3) δ 7.88-7.64 (m, 2H), 7.49-7.43 (m, 2H), 7.30-7.17 (m, 5H), 7.16-7.06 (m, 2H),
6.99 (s, 1H), 6.86-6.74 (m, 2H), 4.29-4.20 (m, 1H), 4.14-3.94 (m, 3H), 3.90-3.82 (m,
1H), 3.51-3.43 (m, 1H), 2.12-2.00 (m, 1H), 1.72-1.64 (m, 1H), 0.67 (s, 9H), -0.22 (s,
3H), -0.60 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 148.6, 144.2, 140.7,
13
135.2, 132.3, 129.7, 129.2, 128.6, 128.5, 128.3, 114.6, 75.4, 65.1, 44.1, 35.8, 32.7,
25.8, 21.7, 17.7, -4.4, -5.7 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for
C32H38ClN2O5SSi, 625.1954; found, 625.1957.
N-benzyl-N-((4aS,5R)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4-phenyl-4a,5,7,8-
tetrahydro-1H,6H-pyrido[1,2-c][1,3]oxazin-3-yl)-4-chlorobenzenesulfonamide (10m).
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Foam solid (96 mg, 50%). [α]D +53.4 (c 1.18, CHCl3); IR (film): νmax 3030, 2951,
2928, 2856, 1731, 1682, 1647, 1362, 1219, 1167, 772, 656 cm-1; 1H NMR (400 MHz,
CDCl3) δ 8.02-7.68 (m, 2H), 7.53-7.41 (m, 2H), 7.28-7.20 (m, 6H), 7.18-7.00 (m, 3H),
6.78 (s, 1H), 4.28-4.17 (m, 2H), 4.12-3.94 (m, 1H), 3.92-3..86 (m, 1H), 3.77-3.68 (m,
1H), 2.77-2.67 (m, 1H), 2.13-2.05 (m, 1H), 1.80-1.67 (m, 2H), 1.51-1.41 (m, 1H),
0.55 (s, 9H), -0.12 (s, 3H), -0.23 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ
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150.7, 140.0, 137.4, 133.9, 130.1, 129.3, 129.1, 128.7, 128.4, 128.1, 127.6, 72.4, 65.3,
52.5, 46.1, 35.7, 25.6, 23.1, 17.8, -4.3 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+
calcd for C33H40ClN2O5SSi, 639.2110; found, 639.2114.
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N-benzyl-N-((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-4-hexyl-1-oxo-4a,5,6,7-t
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etrahydro-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamide
(9n).
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Colorless Oil (114 mg, 62%). [α]D24 +31.8 (c 2.00, CHCl3); IR (film): νmax 3033, 2955,
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2929, 2857, 17335, 1640, 1219, 1165, 838, 772, 673 cm-1; H NMR (400 MHz,
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CDCl3, rotamers) δ 7.84-7.73 (m, 2H), 7.36-7.24 (m, 7H), 4.68-4.58 (m, 1H),
4.00-3.86 (m, 2H), 3.82-3.74 (m, 1H), 3.47-3.29 (m, 2H), 2.43 (m, 3H), 2.24-2.12 (m,
1H), 2.06-1.93 (m, 1H), 1.74-1.46 (m, 2H), 1.45-1.34 (m, 1H), 1.34-1.14 (m, 5H),
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1.03-0.86 (m, 5H), 0.84 (s, 9H), 0.10--0.10 (m, 6H) ppm; C{1H} NMR (100 MHz,
CDCl3) δ 148.9, 144.4, 135.6, 134.8, 134.6, 130.1, 129.9, 129.8, 129.7, 128.7, 128.6,
128.3, 128.2, 118.0, 75.8, 62.5, 50.8 (51.8), 43.3 (43.1), 32.0 (32.2), 29.8 (29.9), 27.8
(28.0), 27.4 (27.2), 25.8, 22.8, 21.7, 17.8, 14.2, -4.0, -4.6 ppm; HRMS (ESI-Orbitrap)
m/z: [M + H]+ calcd for C33H49N2O5SSi, 613.3126; found, 613.3121.
N-benzyl-N-((4aR,5S)-5-((tert-butyldimethylsilyl)oxy)-1-oxo-4a,5,6,7-tetrahydr
o-1H-pyrrolo[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamide (9o). Colorless oil
(114 mg, 72%). The data of major product: IR (film): νmax 3032, 2952, 2928, 2854,
1738, 1645, 1219, 1166, 838, 773, 672 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.79-7.75
(m, 2H), 7.35-7.27 (m, 7H), 5.16 (d, J = 2.0 Hz, 1H), 4.63 (d, J = 13.6 Hz, 1H), 4.30
(d, J = 14.0 Hz, 1H), 3.74 (dd, J = 1.6, 8 Hz, 1H), 3.61-3.47 (m, 2H), 3.47-3.39 (m,
1H), 2.44 (s, 3H), 2.09-2.00 (m, 1H), 1.72-1.63 (m, 1H), 0.84 (s, 9H), -0.02 (s, 3H),
13
-0.03 (s, 3H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 148.6, 144.5, 140.9, 135.8,
134.8, 130.0, 129.1, 128.6, 128.2, 127.9, 102.8, 75.7, 61.0, 50.9, 43.5, 31.1, 25.8, 21.8,
18.0, -4.6, -4.7 ppm;
General Procedure for Synthesis of 15 and 16. To a solution of 12 (0.3 mmol)
or 13 (0.3 mmol) and 143 (0.36 mmol) in dry DCM (2 mL) was added dropwise
.
BF3 Et2O (76 μL, 0.6 mmol) at -78oC. The reaction was allowed to warm to -45 oC
slowly and stirred for 2 h at -45 oC. Saturated aqueous NaHCO3 (2 mL) was added to
quench the reaction. The mixture was extracted with DCM (5 × 3) and the combined
organic layers were washed with brine. Dried, filtered, and concentrated, the residue
was purified by flash chromatography on silica gel (PE/EA = 2:1) to give 15 or 16.
(S)-3-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-4-phenyl-4a,5,6,7-tetrahydro-1H-pyrr
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olo[1,2-c][1,3]oxazin-1-one (15a). Foam solid (83 mg, 71%, d.r. = 73:27). The data
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of major product: [α]D +14.4 (c 1.03, CHCl3); IR (film): νmax 3024, 2951, 2918,
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8
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1897, 1731, 1649, 1217, 1066, 769, 702 cm-1; H NMR (400 MHz, CDCl3) δ
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7.40-7.34 (m, 3H), 7.34-7.28 (m, 3H), 7.19-7.16 (m, 2H), 7.13-7.09 (m, 2H), 4.36 (dd,
J = 10.8, 4.4 Hz, 1H), 4.17-4.12 (m, 1H), 4.06-3.97 (m, 1H), 3.95-3.90 (m, 1H),
3.76-3.68 (m, 1H), 3.56-3.49 (m, 1H), 3.10 (dd, J = 13.6, 6.0 Hz, 1H), 2.72 (dd, J =
14.0, 8.0 Hz, 1H), 2.01-1.92 (m, 1H), 1.90-1.84 (m, 1H), 1.80-1.74 (m, 1H), 1.54-1.44
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(m, 1H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 155.3, 148.3, 135.8, 135.2, 132.9,
129.0, 128.9, 128.5, 127.9, 127.4, 113.9, 68.3, 59.2, 55.9, 46.3, 39.6, 32.4, 22.2 ppm;
HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C23H23N2O4, 391.1652; found,
391.1654.
(S)-3-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-4-(p-tolyl)-4a,5,6,7-tetrahydro-1H-py
rrolo[1,2-c][1,3]oxazin-1-one (15b). Foam solid (112 mg, 92%, d.r. = 71:29). The
data of major product: [α]D24 +19.1 (c 1.04, CHCl3); IR (film): νmax 3029, 2961, 2919,
1731, 1647, 1214, 1066, 750, 701 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.33-7.27 (m,
2H), 7.27-7.25 (m, 1H), 7.19-7.14 (m, 2H), 7.14-7.09 (m, 2H), 7.08-7.03 (m, 2H),
4.33 (dd, J = 11.2, 4.8 Hz, 1H), 4.18-4.13 (m, 1H), 4.07-3.96 (m, 1H), 3.96-3.90 (m,
1H), 3.76-3.67 (m, 1H), 3.56-3.48 (m, 1H), 3.10 (dd, J = 13.6, 6.0 Hz, 1H), 2.72 (dd,
J = 13.6, 7.6 Hz, 1H), 2.35 (s, 3H), 2.00-1.90 (m, 1H), 1.90-1.74 (m, 2H), 1.52-1.41
13
(m, 1H) ppm; C{1H} NMR (100 MHz, CDCl3) δ 155.3, 148.3, 138.4, 135.6, 135.3,
129.9, 129.6, 129.1, 128.9, 127.7, 127.3, 113.9, 68.3, 59.2, 55.9, 46.3, 39.7, 32.4, 22.2,
21.4 ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C24H25N2O4, 405.1809;
found, 405.1809.
(S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-4-(4-chlorophenyl)-4a,5,6,7-tetrahydr
o-1H-pyrrolo[1,2-c][1,3]oxazin-1-one (15c). Foam solid (101 mg, 79%, d.r. = 72:28),
mp, 210-212. The data of major product: [α]D24 +35.2 (c 1.59, CHCl3); IR (film): νmax
3029, 2953, 2919, 2850, 1731, 1682, 1647, 1217, 1065, 770, 703 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.37-7.28 (m, 5H), 7.17-7.09 (m, 4H), 4.34 (dd, J = 10.8, 4.0 Hz, 1H),
4.26-4.20 (m, 1H), 4.20-4.10 (m, 1H), 3.99-3.91 (m, 1H), 3.76-3.67 (m, 1H),
3.57-3.50 (m, 1H), 3.12 (dd, J = 13.6, 6.0 Hz, 1H), 2.74 (dd, J = 13.6, 7.6 Hz, 1H),
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2.03-1.93 (m, 1H), 1.89-1.76 (m, 2H), 1.50-1.40 (m, 1H) ppm; C{1H} NMR (100
MHz, CDCl3) δ 155.1, 148.0, 136.2, 135.1, 134.4, 131.5, 129.4, 129..2, 129.1, 129.0,
127.5, 112.8, 68.4, 59.1, 55.9, 46.4, 39.7, 32.4, 22.3 ppm; HRMS (ESI-Orbitrap) m/z:
[M + H]+ calcd for C23H22ClN2O4, 425.1263; found, 425.1264.
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(S)-3-((R)-4-Isopropyl-2-oxooxazolidin-3-yl)-4-phenyl-4a,5,6,7-tetrahydro-1H-p
yrrolo[1,2-c][1,3]oxazin-1-one (15d). Foam solid (83 mg, 81%, d.r. = 75:25). IR
(film): νmax 3032, 2954, 2928, 2854, 1731, 1682, 1649, 1219, 1063, 771, 702 cm-1; 1H
NMR (400 MHz, CDCl3, d.r. = 75:25) δ 7.40-7.32 (m, 4H), 7.29-7.27 (m, 1H),
4.61-4.55 (m, 1H), 4.15-4.09 (m, 1H), 3.99-3.94 (m, 1H), 3.82-3.74 (m, 1H),
3.64-3.52 (m, 2H), 2.06-1.97 (m, 1H), 1.97-1.85 (m, 3H), 1.68-1.56 (m, 1H), 0.90 (d,
J = 7.2 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3, d.r.
= 75:25) δ 156.1, 148.5, 136.9, 133.0, 128.9, 128.8, 128.7, 128.6, 128.2, 128.1, 113.5,
65.0 (64.3), 60.1 (61.2), 59.5 (59.8), 46.4 (46.3), 32.5 (32.4), 30.3 (29.1), 22.3 (22.2),
18.2, 15.8 (14.7) ppm; HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C19H23N2O4,
343.1652; found, 343.1654.
(S)-3-((R)-2-oxo-4-Phenyloxazolidin-3-yl)-4-phenyl-4a,5,6,7-tetrahydro-1H-pyrr
olo[1,2-c][1,3]oxazin-1-one (15e). Foam solid (91 mg, 81%, d.r. = 74:26). The data of
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major product: [α]D -39.3 (c 1.50, CHCl3); IR (film): νmax 3032, 3023, 1731, 1682,
1
1649, 1219, 771, 702 cm-1; H NMR (400 MHz, CDCl3) δ 7.42-7.36 (m, 3H),
7.36-7.32 (m, 3H), 7.19-7.15 (m, 2H), 7.02-6.97 (m, 2H), 4.80-4.70 (m, 1H),
4.54-4.48 (m, 1H), 4.40 (dd, J = 11.2, 4.4 Hz, 1H), 4.17-4.11 (m, 1H), 3.72-3.63 (m,
1H), 3.52-3.44 (m, 1H), 1.96-1.87 (m, 1H), 1.82-1.70 (m, 2H), 1.47-1.36 (m, 1H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 155.3, 148.4, 136.0, 135.9, 132.7, 129.5, 129.2,
128.7, 128.5, 128.4, 128.0, 113.7, 70.3, 59.5, 59.3, 46.2, 32.3, 22.2 ppm; HRMS
(ESI-Orbitrap) m/z: [M + H]+ calcd for C22H21N2O4, 377.1495; found, 377.1500.
(S)-3-((4R,5S)-5-Methyl-2-oxo-4-phenyloxazolidin-3-yl)-4-phenyl-4a,5,6,7-tetra
hydro-1H-pyrrolo[1,2-c][1,3]oxazin-1-one (15f). Foam solid (80 mg, 68%, d.r. =
1
75:25). IR (film): νmax 3033, 2954, 2928, 2899, 1735, 1649, 1065, 759, 702 cm-1; H
NMR (400 MHz, CDCl3, d.r. = 75:25) δ 7.40-7.36 (m, 4H), 7.32-7.26 (m, 4H),
6.91-6.86 (m, 2H), 5.44 (d, J = 8.4 Hz, 1 H), 4.63 (dd, J = 11.6, 5.2 Hz, 1H),
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4.43-4.33 (m, 1H), 3.82-3.73 (m, 1H), 3.60-3.51 (m, 1H), 2.06-1.91 (m, 3H),
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6
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4.43-4.33 (m, 1H), 0.83 (d, J = 6.4 Hz, 3H) ppm; C{1H} NMR (100 MHz, CDCl3,
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8
9
d.r. = 75:25) δ 154.9 (156.3), 148.4 (148.5), 135.8 (135.2), 134.6 (134.4), 133.0
(133.1), 129.2, 128.9, 128.8, 128.5, 128.4, 128.3, 127.8, 126.5, 126.5, 114.4 (116.9),
79.6 (80.0), 59.5 (59.9), 54.7 (55.9), 46.4 (46.3), 32.5 (32.3), 22.2, 14.9 (14.6) ppm;
HRMS (ESI-Orbitrap) m/z: [M + H]+ calcd for C23H23N2O4, 391.1652; found,
391.1652.
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N-benzyl-N-((4aS,5R)-5-Hydroxy-1-oxo-4-phenyl-4a,5,7,8-tetrahydro-1H,6H-py
rido[1,2-c][1,3]oxazin-3-yl)-4-methylbenzenesulfonamide (11). To a solution of
ent-10a in THF (1 mL) was added HF.Py (2 mL) at room temperature. The reaction
was stirred for 2 h at the same temperature. Saturated aqueous solution of NaHCO3
was carefully added to quench the reaction and extracted with EtOAc (10 mL × 3),
and the combined organic layers were washed with brine. Dried, filtered, and
concentrated, the resides was purified by flash chromatography on silica gel (PE: EA
o
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= 1:1) to give white solid 11 (77 mg, 95%), mp 168-170 C. [α]D -91.9 (c 1.04,
CHCl3); IR (film): νmax 3029, 2944, 2932, 2863, 1715, 1682, 1649, 1163, 768, 671
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.85-7.76 (m, 2H), 7.36-7.31 (m, 2H), 7.29-7.25
(m, 3H), 7.24-7.18 (m, 1H), 7.16-7.06 (m, 4H), 6.89-6.79 (m, 2H), 4.32-4.21 (m, 2H),
4.12-3.92 (m, 1H), 3.76 (d, J = 9.2 Hz, 1H), 3.72-3.53 (m, 1H), 2.73-2.64 (m, 1H),
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2.45 (s, 3H), 2.10-2.02 (m, 1H), 1.80-1.72 (m, 1H), 1.45-1.25 (m, 2H) ppm; C{1H}
NMR (100 MHz, CDCl3) δ 149.8, 144.6, 137.8, 135.5, 134.0, 133.7, 129.8, 129.4,
128.7, 128.6, 128.4, 128.2, 116.6, 72.4, 65.3, 51.7, 45.9, 33.4, 23.3, 21.8 ppm; HRMS
(ESI-Orbitrap) m/z: [M + H]+ calcd for C28H29N2O5S, 505.1792; found, 505.1794.
1
13
Supporting Information: Copies of H, C{1H} NMR spectra and X-ray structural
data (CIF) (9a; 11; 15c). The Supporting Information is available free of charge on
the ACS Publications website at http://pubs.acs.org.
Accession Codes
CCDC 1873700, 1873701, 1873704 contain the supplementary crystallographic data
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for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk,
or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Author information
Corresponding Author
*E-mail: bgwei1974@fudan.edu.cn
Notes
The authors declare no competing financial interest.
Acknowledgment. We thank the National Natural Science Foundation of China
(21472022, 21772027 to B.-G. Wei) and (21702032 to C.-M. Si) for financial support.
The authors also thank Dr Han-Qing Dong (Arvinas, Inc.) for helpful suggestions.
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