Stereoselective Intermolecular [4+2] Process of N,O-acetals with Terminal Alkynes for Construction of Functional cis-Pyrido and Pyrrolo[1,2-c][1,3]oxazin-1-ones

Article abstract of DOI:10.1002/adsc.201901141

A diastereoselective approach to access cis-pyrido and pyrrolo[1,2-c][1,3]oxazin-1-ones has been developed through a one-pot BF₃ ^.Et₂O-catalyzed [4+2] process starting with N,O-acetals and terminal alkynes. In addition, the utility of this transformation is demonstrated by the scalable synthesis of (+)-Febrifugine in 7 steps from the N,O-acetal (15% overall yield). (Figure presented.).

Full text of DOI:10.1002/adsc.201901141

Title: Stereoselective Intermolecular [4+2] Process of N,O-acetals with
Terminal Alkynes for Construction of Functional cis-Pyrido and
Pyrrolo[1,2-c][1,3]oxazin-1-ones
Authors: Chen Wang, Zhuo-Ya Mao, Yi-Wen Liu, Qiao-E Wang,
Chang-Mei Si, Bang-Guo Wei, and Guo-Qiang Lin
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901141
Link to VoR: http://dx.doi.org/10.1002/adsc.201901141

Advanced Synthesis & Catalysis
10.1002/adsc.201901141
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Stereoselective Intermolecular [4+2] Process of N,O-acetals with
Terminal Alkynes for Construction of Functional cis-Pyrido
and Pyrrolo[1,2-c][1,3]oxazin-1-ones
a
a
a
b
a,
Chen Wang, Zhuo-Ya Mao, Yi-Wen Liu, Qiao-E Wang, Chang-Mei Si, * Bang-Guo
a,
c
Wei * and Guo-Qiang Lin
a
School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, People’s Republic of China
Beijing Key Lab of Plant Resource Research and Development, Beijing Technology and Business University, Beijing
b
1
00048, People’s Republic of China
c
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
People’s Republic of China
E-mail: sicm@fudan.edu.cn; bgwei1974@fudan.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A diastereoselective approach to access cis-pyrido
and pyrrolo[1,2-c][1,3]oxazin-1-ones has been developed Keywords: cis-Pyrido and Pyrrolo[1,2-c][1,3]oxazin-1-
.
through a one-pot BF
3
Et
2
O-catalyzed [4+2] process starting ones; Terminal alkyne; N,O-acetal; Intermolecular [4+2]
with N,O-acetals and terminal alkynes. In addition, the utility process; Febrifugine
of this transformation is demonstrated by the scalable
synthesis of (+)-Febrifugine in 7 steps from the N,O-acetal
(
15% overall yield).
OH
N
O
Br
Cl
Introduction
OH
N
O
O
O
N
N
The development of efficient and highly selective
methodology to versatile skeletons for bioactive
molecules is of paramount importance in modern
N
N
H
H
(+)-Febrifugine (1)
(
+)-Halofuginone (3)
[
1]
organic and pharmaceutical synthesis. Nitrogen-
containing heterocycles, with wide existence in
nature, are useful subunits in these fields. Pyrido and
pyrrolo[1,2-c][1,3]oxazin-1-ones (cis- or trans-), as
[H+]
EtOH
N
O
OTBS
OTBS
O
OH
O
N
N
[
2]
N
well as 3-hydroxy-2-substituted piperidine scaffold,
N
TMS
H
serve as building blocks and core skeletons for
numerous alkaloids, pharmaceutical candidates and
drugs through valuable contributions to the synthetic
and medicinal chemistry. As a prime instance,
antimalarial alkaloids (+)-Febrifugine 1 and (+)-
IsoFebrifugine 2 (Figure 1), isolated from Chinese
medicinal plants Dichroa febrifuga Lour. (Chang
H
O
O
(+)- isofebrifugine (2)
Michael and Retro-Michael Process
7
m
4
Figure 1. Natural products containing pyrido [1,2-
c][1,3]oxazine skeleton equivalent 4.
[3]
[4]
Shan ) and related hydrangea plants, contain the
Owing to the existence of β-amino ketone moiety
in the structure, (+)-Febrifugine 1 and (+)-
Halofuginone 3 are easily transformed into their
corresponding hemiketal forms (+)-Iso-febrifugine 2
typical 3-hydroxy-2-substituted piperidine scaffold.
+)-Halofuginone[ 3 (named Tempostatin), a multi-
5,6]
(
adaptive pharmaceutical candidate analogous to
[7]
[11]
Febrifugine, can effectively fight against fibrosis,
and is currently in phase II clinical trials for treatment
of scleroderma in human. In addition, it plays a vital
role in inhibiting the growth of cancer cells. Very
recently, (+)-Halofuginone 3 has also been selected
for further investigation as the candidate for treatment
of knee arthritis in pre-clinical research.[10]
and (+)-Iso-halofuginone under acidic conditions,
causing great difficulties in their preparation,
especially for the scalable synthesis. During the past
30 years, asymmetric synthesis of (+)-Febrifugine 1
or (+)-Halofuginone 3 has attracted wide attention
[8]
[9]
and a number of powerful approaches have been
[12]
reported.
Currently, almost all synthetic
approaches started from chiral 3-hydroxy-2-
substituted piperidine scaffold. During the past
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201901141
decade, we have made significant efforts to pursue
the chiral building block 5-hydroxy-6-substituted
piperidine lactam[ and scalable synthesis of (+)-
Halofuginone 3. As a result, trans- chiral piperidine
skeleton could be obtained through continuous
and bioactive molecules, we decided to investigate
the reaction of N,O-acetal 5a with terminal alkyne.
Herein we present an efficient asymmetric approach,
through intermolecular [4+2] process of N,O-acetal
5a with terminal alkynes, to access cis-pyrido and
pyrrolo[1,2-c][1,3]oxazin-1-ones, and its application
in concise synthesis of (+)-Febrifugine 1.
13]
addition-deprotection-cyclization
from
α-chiral
aldimine.[
14]
In addition, cis- chiral piperidine 4
[15]
could be achieved by nucleophilic substitution of
N,O-acetal, from which one kilogram of (+)-
Halofuginone 3 was prepared for clinical use. Results and Discussion
[16]
Alkynes are widely utilized in organic synthesis.
For example, SnCl could effectively catalyze the
intramolecular addition of N-acyloxyiminium ions
4
Our investigation started with the reaction of N,O-
[19,20a]
acetal 5a
known catalysts SnCl
examined, and the results showed that catalytic
with phenylacetylene 6a. First, well-
17a]
[17a,c] [18]
(
Scheme 1, 1);[
promote intermolecular
alkynylarenes and N,O-acetals (Scheme 1, 2/3).
SnCl
4
or Bi(OTf)
3
could also
of
4
and Bi(OTf)
3
were
carboarylation
[
17c,18]
amount of Bi(OTf) could give the desired product 7a
3
Enlightened by pioneering results, our group recently
achieved an effective approach to access
functionalized pyrido and pyrrolo[1,2-c][1,3]oxazin-
in 9% yield, along with excellent diastereoselectivity
(dr > 99:1) (Table 1, entries 1-3). Although catalytic
amount of Zn(OTf) and stoichiometric CuI failed to
2
1
-ones through nucleophilic addition-cyclization
initiate the intermolecular addition (Table 1, entries
process of N,O-acetals with ynamides (Scheme 1,
4-5), stoichiometric Cu(OTf)
2
could promote the
[19]
4).
Unfortunately, further efforts to deliver (+)-
reaction to afford the desired product 7a in 48% yield
with low diastereoselectivity (Table 1, entry 6). To
further improve the yield and diastereoselectivity,
more catalysts were screened.
Halofuginone 3 or (+)-Febrifugine 1 failed due to the
difficulty in manipulating the amide C-N bond for
chain elongation under mild conditions.
Intramolecular addition-cyclization process[17a]
Table 1. Optimization of reaction conditions.
H
OTBS
OTBS
Ph
COOMe (1)
SnCl4
Lewis Acid
N
AcO
COOMe
Ph
N
TMS
N
OMe
N
Boc
TMS
O
O
Intermolecular addition-cyclization process[17c,18]
Boc
O
O
O
OEt
Ph
5a
6a
7a
O
O
TMS
SnCl4
(2)
EtO
N
Entrya)
o
cis:transc)
N
Ph
Lewis Acid
(equiv.)
SnCl (1.2)
Bi(OTf) (0.1) r.t
Bi(OTf) (0.1) r.t~80
T C
Yield
[%]
TMS
b)
Ph
Ph
O
R1
1
2
3
4
5
6
7
8
9
4
-78~rt trace
--
--
99:1
--
--
80:20
80:20
80:20
99:1
--
99:1
99:1
99:1
99:1
R1
X
X
trace
9
NR
NR
48
28
49
<10
3
+
Bi(OTf)3
NP
(
3)
3
R2 PN
Zn(OTf)
CuI (1.0)
Cu(OTf)
2
(0.1) r.t
r.t
(1.0) r.t
(0.1) r.t
(0.1) r.t
r.t
OH
P = Me or Bn)
R2
(
O
Our Previous Intermolecula .r addition-cyclization process[19]
2
Er(OTf)
Sc(OTf)
AuCl (0.1)
3
OTBS
R1
OTBS
OMe
3
R3
.
R1
BF3 Et2O
3
N
o
N
(4)
N
R2
-78~-45 C
10
11
2
3
4
TMSOTf (1.0) -78~r.t NR
BF Et O (1.0) -50~r.t 12
R3
Boc
O
O
N
R2
.
dr up to 99:1
3
3
3
3
2
2
2
2
.
.
.
1
1
1
BF
BF
BF
Et
Et
Et
O (2.0) -50~r.t 69
O (3.0) -50~r.t 65
O (2.0) -78~-45 42
trans-form
This Work ( Intermolecular [4+2] cycloaddition process)
(
)n
OTBS
(
)n
OTBS
OMe
a)
Typical reaction conditions: Lewis acid was added to a
mixture of compound 5a (100 mg, 0.29 mmol) and 6a
0.58 mmol, 2 equiv.) in solvent (1.5 mL) at -50 C. After
stirring for 0.5 h, the reaction mixture was slowly warmed
to rt and then quenched with saturated aqueous NaHCO
solution.
.
BF3 Et O
2
R
H
N
(5)
N
dr up to 99:1
o
(
Boc
O
O
R
R = Alkyl, aryl
5
a
cis-form
3
b)
Scheme 1. Our strategy to access cis-pyrido and
pyrrolo[1,2-c][1,3]oxazin-1-ones.
Isolated yield.
c)
dr were determined by 1H NMR Spectra of crude
products.
In order to achieve our ultimate goal to find useful
building blocks for the synthesis of natural products
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201901141
The results from catalytic amount of Er(OTf)
3
,
Scheme 2. Reactions of N,O-acetal 5a with Different
Terminal Alkynes.
Sc(OTf)
3
and AuCl
3
(Table 1, entries 7-9) were
unsatisfactory, and TMSOTf could not generate any
.
desired product 7a (Table 1, entry 10). BF
3
2
Et O
proved to be the best choice for this transformation.
under our optimized conditions. When trimethyl-
(prop-2-ynyl)silane was examined, the desired
product 7m was obtained in 69% yield with excellent
diastereoselectivity. Other aliphatic terminal alkynes
.
Although stoichiometric BF
3
Et
O significantly increased
the yield to 69%, along with excellent
2
O gave low yield of
.
7
a, 2 and 3 equiv. BF
3
Et
2
diastereoselectivity (Table 1, entries 11-13). However, 6h-6l also afforded the desired products in moderate
o
o
conducting the reaction at -78 C to -45 C led to
lower yield of 42%, albeit still with high
diastereoselectivity (dr > 99:1) (Table 1, entry 14).
yields and with excellent diastereoselectivities (7h-7l).
It is worth mentioning that diynes 6k and 6l could
successfully provide the products 7k and 7l in
moderate yields with excellent diastereoselectivities
(dr > 99:1). The stereochemistry of the products
Next, we turned to investigate the scope and
limitation of this reaction for N,O-acetal 5a with
different terminal alkynes 6a-6m. First, different
substituted phenylacetylenes 6a-6g were surveyed
under the optimal conditions, as summarized in
Scheme 2. In general, the reactions with various
substituted phenylacetylenes 6a-6g proceeded
pyrido[1,2-c][1,3]oxazin-1-ones
7a-7m
were
unambiguously assigned as cis-form by X-ray
[
22,23]
crystallographic analysis of ent-7f
.
X
X
.
BF3 Et O
2
R
N
O
o
N
smoothly in moderate yields, except
for 2-
-50 C~r.t DCM
Boc
chlorophenylacetylene (7g, 38%). Excitedly, the
diastereoselectivities in our cases were excellent (dr >
O
O
R
8
a, X=H
8b-8m, X=OTBS
b-9m, X=OH
5b, X=H
6a-6h, 6j-6m
5c, X=OTBS
9
9:1). Alphatic alkyl substituted terminal alkynes
c
9
(
6h-6m) also worked well
OH
1
OTBS
9b, R = H, 69%, dr > 99:1
OTBS
.
N
1
BF3 Et O
9c, R = Me, 72%, dr > 99:1
2
R
N
1
9
9
e, R = Br, 65%, dr > 99:1
o
N
O
O
N
O
-50 C~rt, DCM
1
g, R = Cl, 54%, dr > 99:1
O
O
Boc
1
O
O
R
9i, R = MeO, 54%, dr > 99:1
5
a
6a-6m
7a-7m
8a, 75%, dr > 99:1
R1
OH
OH
OTBS
OTBS
2
7
7
c, R = Me, 77%, dr > 99:1
N
N
N
N
2
R2
e, R =2 Br, 63%, dr > 99:1
O
O
R
O
O
O
O
O
O
R1
OTBS
9d, R = Me, 73%, dr > 99:1
2
9l, 51%, dr > 99:1
2
1
9f, R = Br, 53%, dr > 99:1
7
7
7
7
a, R = H, 70%, dr > 99:1
b, R1 = Me, 72%, dr > 99:1
d, R = Br, 57%, dr > 99:1
f, R1 = Cl, 65%, dr > 99:1
OH
OH
OH
N
1
TMS
O
O
N
N
N
7
m, 69%, dr > 99:1d
OTBS
R3
O
O
O
O
O
O
OTBS
OTBS
Cl
3
N
9j, R = n-C H11, 77%, dr > 99:1
6
9m, 53%, dr > 99:1
9
a)
h, 49%, dr > 99:1 9k, R3 = t-Bu, 76%, dr > 99:1
N
N
O
O
3 2
The reactions were performed with BF ·Et O (1.00
mmol), N,O-acetal 5b (0.50 mmol) and alkynes (1.00
mmol) in dry DCM (1.5 mL) at -50 C for 0.5 h, then the
reaction mixture was slowly warmed to rt and quenched
O
O
O
O
Cl
7g, 38%, dr > 99:1
7h, 70%, dr > 99:1
7i, 69%, dr > 99:1
o
OTBS
OTBS
OTBS
with saturated aqueous NaHCO
The reactions were performed with BF
mmol), N,O-acetal 5c (0.30 mmol) and alkynes (1.00
mmol) in dry DCM (1.5 mL) at -50 C for 0.5 h, then the
reaction mixture was slowly warmed to rt and quenched
3
solution.
N
O
N
N
b)
3
2
·Et O (0.60
O
O
O
O
O
o
7
a)
j, 63%, dr > 99:1
7k, 54%, dr > 99:1
7l, 51%, dr > 99:1
3 2
The reactions were performed with BF ·Et O (0.58
mmol), N,O- acetal 5a (0.29 mmol) and alkyne (0.58
mmol) in dry DCM (1.5 mL) at -50 C for 0.5 hour, then
the reaction mixture was slowly warmed to r.t and
with saturated aqueous NaHCO
3
solution.
c)
o
The reactions were performed with BF
3
·Et
2
O (2.0 eq.),
8
b-8m (1.0 eq.) in MeCN (1.5 mL) at rt for 1h.
Isolated yield.
d)
e)
dr were determined by 1H NMR
quenched with saturated aqueous NaHCO
3
solution.
b)
Spectra of crude products.
Isolated yield.
c)
dr were determined by 1H NMR Spectra of crude
Scheme 3. Reactions of N,O-acetals 5b/5c with Different
Terminal Alkynes.
products.
d)
Larger scale synthesis of compound 7m was conducted
from 5a (5.04 g) with 65% yield.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201901141
Then the scope and limitation of N,O-acetals 5b and
[19,20b]
H
5c
with different terminal alkynes 6a-6l were
H
N
N
O
LA
O
also examined (Scheme 3). First, the reaction of N,O-
acetal 5b with phenylacetylene 6a successfully
delivered the desired product 8a in 75% yield. The
reactions of chiral N,O-acetal 5c with different
substituted phenylacetylenes 6a-6g were also
examined. Due to the difficulty in separating the
desired products from trace amount of substrates
using silica gel flash chromatography, the crude
5
a
OTBS
OTBS
O
O
steric hindrance favored
steric hindrance disfavored
a
b
R
H
H
disfavoured attack
H
N
O
H
reaction mixtures were treated with additional 2 equiv.
OTBS
R
N
.
O
BF
3
Et
2
O to afford the corresponding deprotected
O
OTBS
favoured attack
R
compounds 9b-9i in good isolated yields with
excellent diastereoselectivities (dr > 99:1). Aliphatic
alkyl substituted terminal alkynes (6h, 6j-6l) also
worked well under our optimized conditions. When
O
c
d
OTBS
R
OTBS
1
-octyne and 3,3-dimethylbut-1-yne were examined
respectively, the desired products 9j and 9k were
obtained in good yields and with excellent
diastereoselectivities (dr > 99:1). Similarly, diynes
could also produce the desired products 9l and 9m in
moderate yields with excellent diastereoselectivities
N
N
O
O
O
O
R
cis-7
trans-7
Figure 2. Possible mechanism for BF .
4+2] process.
3
2
Et O-catalyzed
(
dr > 99:1). The stereochemistry of pyrrolo[1,2-
[
c][1,3]oxazin-1-ones 9b-9m was unambiguously
assigned as cis-form by X-ray crystallographic
analysis of compound 9g[
.
22]
With chiral cis-pyrido [1,2-c][1,3]oxazin-1-one 7m in
hand, we focused on the scalable synthesis of (+)-
Febrifugine (1). The reaction of N,O-acetal 5a with
trimethyl(prop-2-ynyl)silane 6m gave 7m in 69%
yield with excellent diastereoselectivity (dr > 99:1).
Ring opening and simultaneous removal of TMS
.Et
A possible mechanism for this BF
3
2
O-catalyzed
[
4+2] process was illustrated in Figure 2. When N,O-
acetal 5a reacted with terminal alkynes 6, diene type
of imide onium was first generated under Lewis acid
conditions. Conformation b is more stable than a due
to allylic strain considerations where it is preferred to
[21]
group with KOH gave crude amine,
which was
[17d]
protected as benzyl carbamate 10 in 70% yield.
Treatment of 10 with TMSOTf in the presence of
N,N-diisopropylethylamine (DIPEA) and subsequent
bromination with NBS afforded α-bromoketone 11 in
have the α-H coplanar to the double bond.
However, in [4+2] cycloaddition with alkyne, the
smaller steric hindrance conformation a is easier to
react with. Then, the [4+2] cycloaddition with alkyne
would take place from the less steric side of form c to
7
6% yield. Finally, compound 11 was smoothly
converted to the desired (+)-Febrifugine (1) {mp 124-
generate cis-product 7, along with the release of 2-
o
[11a]
o
25
methylprop-1-ene.[17a-b]
126 C; lit.
mp 133-136 C; [α]
D
= +20.4 (c 0.25,
[
11a]
20
[11d]
EtOH), lit.
[α]
D
= +14.0 (c 0.50, EtOH); lit.
2
7
[
α]
D
= +26.6 (c 0.1, EtOH)} in 42% overall yield
[
15]
according to our previous process : coupling with
-hydroxyquinazoline, deprotection of the TBS and
4
Cbz groups to crude dihydrochloride salt of (+)-
IsoFebrifugine (2), basification and recrystallization
process (Scheme 4). All the spectroscopic and
physical data of the synthetic (+)-Febrifugine (1)
[11a]
were identical to the previous reported results.
OTBS
OTBS
OTBS
O
O
a
b
Br
N
N
N
TMS
Cbz
Cbz
O
c
O
10
11
76%
7
m
7
0% for two steps
OTBS
O
N
OH
N
d
O
N
N
N
N
H
Cbz
O
O
1
2
(+)-Febrifugine (1)
62%
68% for two steps
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201901141
(
4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-p-tolyl-5,6,7,8-
Reagents and conditions: a) (i) KOH, t-BuOH, toluene,
refluxed; (ii) DMAP, CbzCl, TEA, DMF, rt, 70% for two
tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one (7b)
steps; b) TMSOTf, DIPEA, DCM,1 h, then NaHCO
h, 76%; c) 4-hydroxyquinazoline, KOH, EtOH, rt, 62%;
d) 6 N HCl, MeOH, refluxed, 4 h, then EtOH, refluxed, 68% 775 cm ; H NMR (400 MHz, CDCl
3
, NBS,
o
25
White solid (78 mg, 72%), mp 117-119 C; [α]
D
= +74.0
2
(
c 0.10, CH OH); IR (film): νmax 2928, 2855, 1723, 1455,
3
-
1 1
3
) δ 7.56-7.41 (m, 2H),
7
1
1
1
3
.23-7.11 (m, 2H), 5.34-5.19 (m, 1H), 4.46 (d, J = 13.2 Hz,
H), 4.05-3.92 (m, 1H), 3.82-3.67 (m, 1H), 2.85-2.68 (m,
H), 2.34 (s, 3H), 2.17-2.04 (m, 1H), 1.94-1.86 (m, 1H),
.69-1.60 (m, 1H), 1.47-1.40 (m, 1H), 0.79 (s, 9H), 0.01 (s,
for two steps.
Scheme 4. The preparation of (+)-Febrifugine (1).
1
3
1
3
H), -0.11 (s, 3H) ppm; C{ H} NMR (150 MHz, CDCl )
δ 151.0, 149.8, 139.1, 129.3, 129.2, 124.5, 95.6, 68.1, 60.1,
Conclusion
45.6, 32.2, 25.7, 21.4, 18.9, 17.9, -4.6, -4.8 ppm; HRMS
+
(
ESI) m/z: [M+H] Calcd for C21
H
32NO
3
Si: 374.2146,
found: 374.2148.
In summary, we established a novel and efficient
approach for highly diastereoselective synthesis of
cis-pyrido and pyrrolo[1,2-c][1,3]oxazin-1-ones 7, 8
and 9. Such BF
(
4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-m-tolyl-
5,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one
.
Et
2
O-catalyzed reactions underwent
(7c)
3
a [4+2] process from terminal alkynes 6 and N,O-
acetals 5a, 5b and 5c, and chiral pyrido and
pyrrolo[1,2-c][1,3]oxazin-1-ones could also be
obtained in moderate yields and with excellent
diastereoselectivities (dr > 99:1). In addition, the
utility of chiral building block 7m has been
o
25
White solid (83 mg, 77%), mp 112-114 C; [α]
D
= +39.0
); IR (film): νmax 2927, 2855, 1717, 1456,
73 cm ; H NMR (400 MHz, CDCl ) δ 7.49-7.43 (m, 1H),
(
c 0.50, CHCl
3
-1
1
7
3
7.41-7.35 (m, 1H), 7.26-7.21 (m, 1H), 7.18-7.12 (m, 1H),
5
.30 (d, J = 4.4Hz, 1H), 4.47 (d, J = 11.6 Hz, 1H), 3.99 (d,
J = 4.0 Hz, 1H), 3.76-3.72 (m, 1H), 2.82-2.71 (m, 1H),
2
1
.35 (s, 3H), 2.18-2.05 (m, 1H), 1.96-1.87 (m, 1H), 1.70-
.60 (m, 1H), 1.48-1.41 (m, 1H), 0.80 (s, 9H), 0.02 (s, 3H),
demonstrated by a scalable
enantioselective
13
1
synthesis of (+)-Febrifugine (1).
-0.10 (s, 3H) ppm; C{ H} NMR (150 MHz, CDCl
3
) δ
1
6
51.0, 149.8, 138.2, 132.0, 130.0, 128.3, 125.3, 121.8, 96.3,
8.1, 60.1, 45.6, 32.2, 25.7, 21.5, 18.9, 17.9, -4.6, -4.8
+
ppm; HRMS (ESI) m/z: [M+H] Calcd for C21
374.2146, found: 374.2149.
3
H32NO Si:
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 as eluent. Optical rotations were
measured on a polarimeter with a sodium lamp. HRMS
were measured on LTQ-Orbitrap-XL apparatus. IR spectra
were recorded using film on a Fourier Transform Infrared
Spectrometer. NMR spectra were recorded at 400, 500 or
(4aS,5S)-3-(4-Bromophenyl)-5-(tert-
butyldimethylsilyloxy)-5,6,7,8-tetrahydropyrido[1,2-
c][1,3]oxazin-1(4aH)-one (7d)
o
25
White solid (72 mg, 57%), mp 159-160 C; [α]
D
= +65.2
OH); IR (film): νmax 2076, 1637, 1111, 1032,
1
(
c 0.25, CH
3
-1
5
5
89 cm ; H NMR (400 MHz, CDCl
3
) δ 7.50-7.43 (m, 4H),
.32 (d, J = 4.4 Hz, 1H), 4.45 (d, J = 13.2 Hz, 1H), 3.99 (d,
J = 4.4 Hz, 1H), 3.76-3.70 (m, 1H), 2.81-2.71 (m, 1H),
2
1
.17-2.02 (m, 1H), 1.95-1.86 (m, 1H), 1.74-1.59 (m, 1H),
.47-1.41 (m, 1H), 0.78 (s, 9H), 0.01 (s, 3H), -0.12 (s, 3H)
6
00 MHz, and chemical shifts are reported in δ (ppm)
1
referenced to an internal TMS standard for H NMR and
13
1
ppm; C{ H} NMR (150 MHz, CDCl
3
) δ 150.6, 148.8,
1
3
1
3
CDCl (77.16 ppm) for C{ H} NMR.
1
2
31.7, 131.0, 126.1, 123.3, 97.0, 68.0, 60.1, 45.6, 32.1,
+
5.6, 18.9, 17.9, -4.6, -4.8 ppm; HRMS (ESI) m/z: [M+H]
General Procedure for Synthesis of 7 or 8a. To a
solution of N,O-acetal 5a or 5b (100 mg, 1.0 eq.) and 6
Calcd for C20
H
29BrNO
3
Si: 438.1095, found: 438.1097,
440.1075.
(
2.0 eq.) in anhydrous DCM (1.5 mL) was treated with
.
3 2
BF OEt (2.0 eq.) at -50°C under an argon atmosphere.
(
4aS,5S)-3-(3-Bromophenyl)-5-(tert-
After stirring for 0.5 h, the mixture was allowed to warm to
room temperature. The mixture was quenched with
butyldimethylsilyloxy)-5,6,7,8-tetrahydropyrido[1,2-
c][1,3]oxazin-1(4aH)-one (7e)
3
saturated aqueous solution of NaHCO and extracted with
EtOAc for three times. The combined organic layers were
o
25
White solid (80 mg, 63%), mp 133-135 C; [α]
D
= +6.6 (c
2 4
washed with brine and dried over anhydrous Na SO .
0
.50, CHCl ); IR (film): νmax 2925, 2853, 1722, 1455, 774
3
Filtered and concentrated under reduced pressure, the
residue was purified by chromatography on silica gel
-
1
1
cm ; H NMR (400 MHz, CDCl
3
) δ 7.84-7.75 (m, 1H),
.58-7.53 (m, 1H), 7.53-7.47 (m, 1H), 7.32-7.23 (m, 1H),
.37 (d, J = 4.0 Hz, 1H), 4.49 (d, J = 13.2 Hz, 1H), 4.04 (d,
7
5
(
PE/EA=3:1) to give the title compound 7a-7m, 8a.
J = 4.0 Hz, 1H), 3.81-3.77 (m, 1H), 2.88-2.76 (m, 1H),
(
4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-phenyl-
2
1
.21-2.07 (m, 1H), 2.00-1.90 (m, 1H), 1.75-1.60 (m, 1H),
.51-1.46 (m, 1H), 0.83 (s, 9H), 0.05 (m, 3H), -0.07 (s, 3H)
5
,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one
(
7a)
13
1
ppm; C{ H} NMR (150 MHz, CD
3
OD) δ 153.0, 148.6,
1
35.3, 133.1, 131.4, 128.3, 124.1, 123.7, 100.0, 69.3, 61.1,
o
25
White solid (73 mg, 70%), mp 126-128 C; [α]
D
= +45.2
46.4, 32.7, 26.1, 19.8, 18.6, -4.6, -4.8 ppm; HRMS (ESI)
+
(
c 0.50, CHCl ); IR (film): νmax 2950, 2927, 2855, 1717,
3
m/z: [M+H] Calcd for C20
438.1098, 440.1076.
3
H29BrNO Si: 438.1095, found:
-
1 1
1
7
4
3
1
455, 1065, 745 cm ; H NMR (400 MHz, CDCl ) δ 7.67-
3
.57 (m, 2H), 7.43-7.32 (m, 3H), 5.33 (d, J = 4.4 Hz, 1H),
.48 (d, J = 12.8 Hz, 1H), 4.01 (d, J = 4.0 Hz, 1H), 3.79-
.73 (m, 1H), 2.83-2.73 (m, 1H), 2.19-2.04 (m, 1H), 1.98-
.87 (m, 1H), 1.73-1.61 (m, 1H), 1.49-1.42 (m, 1H), 0.80
(
4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-(4-
chlorophenyl)-5,6,7,8-tetrahydropyrido[1,2-
c][1,3]oxazin-1(4aH)-one (7f)
1
3
1
(
(
s, 9H), 0.03 (s, 3H), -0.09 (s, 3H) ppm; C{ H} NMR
125 MHz, CD
3
OD) δ 153.3, 150.1, 133.1, 130.2, 129.5,
25.3, 98.5, 69.3, 61.1, 46.4, 32.8, 26.1, 19.9, 18.6, -4.6, -
o
25
White solid (74 mg, 65%), mp 86-88 C; [α]
D
= +35.0 (c
1
4
C
+
1.00, CH OH); IR (film): ν 2928, 2857, 1730, 1637,
3
max
.8 ppm; HRMS (ESI) m/z: [M+H] Calcd for
Si: 360.1990, found: 360.1989.
-
1 1
1
(
3
492, 775 cm ; H NMR (400 MHz, CD OD) δ 7.55-7.50
m, 2H), 7.41-7.33 (m, 2H), 5.85 (d, J = 3.6 Hz, 1H), 4.28
20
H
30NO
3
5
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201901141
2
5
(
d, J = 13.6 Hz, 1H), 3.76 (dd, J = 9.2, 3.2 Hz, 1H), 3.53-
Colorless oil (55 mg, 54%), [α]
CH OH); IR (film):νmax 2080, 1634, 1083, 1031, 616 cm ;
OD) δ 4.82 (d, J = 4.4 Hz, 1H),
D
= -28.9 (c 1.00,
-1
3
1
0
1
4
.43 (m, 1H), 2.80-2.70 (m, 1H), 2.09-1.99 (m, 1H), 1.76-
.69 (m, 1H), 1.66-1.47 (m, 2H), 0.89 (s, 9H), 0.06 (s, 3H),
3
1
H NMR (400 MHz, CD
3
1
3
1
.05 (s, 3H) ppm; C{ H} NMR (100 MHz, CD
3
OD) δ
4.28-4.22 (m, 1H), 3.93 (d, J = 4.4 Hz, 1H), 3.74-3.71 (m,
1H), 2.84-2.77 (m, 1H), 2.25-2.20 (m, 3H), 2.20-2.14 (m,
2H), 2.02-1.95 (m, 1H), 1.88-1.83 (m, 1H), 1.73-1.64 (m,
3H), 1.44-1.38 (m, 1H), 0.89 (s, 9H), 0.06 (s, 3H), 0.04 (s,
51.2, 147.4, 136.3, 131.6, 129.9, 126.8, 98.7, 74.5, 61.9,
5.7, 35.3, 26.2, 24.0, 18.8, -4.1, -4.5 ppm; HRMS (ESI)
+
m/z: [M+H] Calcd for C20
H
29ClNO
3
Si: 394.1600, found:
13
1
3
94.1603.
3H) ppm; C{ H} NMR (100 MHz, CD
3
OD) δ 153.5,
1
2
52.3, 98.9, 84.1, 70.2, 69.2, 60.7, 46.3, 32.7, 32.1, 26.2,
6.1, 19.9, 18.8, 18.4, -4.5, -4.8 ppm; HRMS (ESI) m/z:
(
4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-(2-
+
[
M+H] Calcd for
19 3
C H32NO Si: 350.2146, found:
chlorophenyl)-5,6,7,8-tetrahydropyrido[1,2-
3
50.2148.
c][1,3]oxazin-1(4aH)-one (7g)
o
25
(4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-(hex-5-ynyl)-
White solid (43 mg, 38%), mp 133-135 C; [α]
D
= +15.0
5
,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one
(
3
c 0.10, CH OH); IR (film): νmax 2065, 1704, 1634, 1558,
-1 1
(7l)
1
(
(
3
489, 649 cm ; H NMR (400 MHz, CDCl ) δ 7.62-7.57
m, 1H), 7.42-7.37 (m, 1H), 7.36-7.27 (m, 2H), 5.53-5.45
2
5
m, 1H), 4.48 (d, J= 12.4 Hz, 1H), 4.08-4.04 (m, 1H),
Colorless oil (54 mg, 51%), [α]
D
= -22.8 (c 1.00,
3
1
0
.80-3.76 (m, 1H), 2.83-2.75 (m, 1H), 2.15-2.07 (m, 1H),
.96-1.89 (m, 1H), 1.71-1.64 (m, 1H), 1.51-1.45 (m, 1H),
3
CH OH); IR (film): νmax 2077, 1637, 1455, 1255, 1177,
-1 1
3
1032, 716 cm ; H NMR (400 MHz, CDCl ) δ 4.57 (d, J =
13
1
.86 (s, 9H), 0.05 (s, 3H), -0.03 (s, 3H) ppm; C{ H}
3.6 Hz, 1H), 4.40 (d, J = 13.2 Hz, 1H), 3.79 (d, J = 3.2 Hz,
1H), 3.64-3.58 (m, 1H), 2.73-2.62 (m, 1H), 2.21-2.16 (m,
2H), 2.15-1.99 (m, 3H), 1.98-1.89 (m, 1H), 1.88-1.82 (m,
1H), 1.65-1.52 (m, 5H), 1.41-1.35 (m, 1H), 0.86 (s, 9H),
NMR (150 MHz, CDCl
3
) δ 150.8, 147.1, 132.1, 131.3,
1
2
30.6, 130.1, 129.9, 126.9, 102.9, 67.9, 60.3, 45.4, 32.1,
+
5.8, 18.9, 18.0, -4.4, -4.7 ppm; HRMS (ESI) m/z: [M+H]
13
1
Calcd for C20
H
29ClNO
3
Si: 394.1600, found: 394.1599.
0.02 (s, 3H), 0.01 (m, 3H) ppm; C{ H} NMR (150 MHz,
CDCl
3
) δ 152.1, 151.1, 96.5, 84.2, 68.6, 67.9, 59.7, 45.4,
3
2.1, 31.9, 28.0, 25.7, 25.1, 18.9, 18.3, 18.0, -4.5, -4.8
(
4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-hexyl-5,6,7,8-
tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one (7h)
+
ppm; HRMS (ESI) m/z: [M+H] Calcd for C20
64.2303, found: 364.2306.
3
H34NO Si:
3
o
25
White solid (75 mg, 70%), mp 82-83 C; [α]
D
= -50.8 (c
(
4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-
1
1
.00, CH
3
OH); IR (film): νmax 2949, 2927, 2883, 2854,
-1 1
((trimethylsilyl)methyl)-5,6,7,8-tetrahydropyrido[1,2-
715, 1455, 775 cm ; H NMR (500 MHz, CD
3
OD) δ 4.80
c][1,3]oxazin-1(4aH)-one (7m)
(
d, J = 3.6 Hz, 1H), 4.31-4.26 (m, 1H), 3.97-3.93 (m, 1H),
3
2
1
0
.77-3.73 (m, 1H), 2.87-2.80 (m, 1H), 2.16-2.09 (m, 2H),
.05-1.98 (m, 1H), 1.91-1.87 (m, 1H), 1.75-1.68 (m, 1H),
.56-1.50 (m, 2H), 1.46-1.42 (m, 1H), 1.39-1.32 (m, 6H),
o
25
White solid (74mg, 69%), mp 116-118 C; [α]
D
= -26.0 (c
OH); IR (film): νmax cm ; H NMR (400 MHz,
3
OD) δ 4.61 (d, J = 4.0 Hz, 1H), 4.30-4.25 (m, 1H),
-
1
1
0.25, CH
CD
3
.93 (s, 3H), 0.92 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H) ppm;
13
1
C{ H} NMR (150 MHz, CD
3
OD) δ 153.6, 153.1, 98.3,
3.91 (d, J = 4.4 Hz, 1H), 3.73-3.70 (m, 1H), 2.88-2.79 (m,
1H), 2.08-1.96 (m, 1H), 1.93-1.84 (m, 1H), 1.75-1.66 (m,
1H), 1.65-1.61 (m, 1H), 1.57-1.51 (m, 1H), 1.44-1.39 (m,
1H), 0.92 (s, 9H), 0.09 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H)
6
1
9.2, 60.7, 46.3, 33.2, 32.7, 28.7, 27.0, 26.3, 26.2, 23.6,
+
9.9, 18.8, 14.4, -4.5, -4.7 ppm; HRMS (ESI) m/z: [M+H]
Calcd for C20
H
38NO
3
Si: 368.2616, found: 368.2619.
13
1
ppm; C{ H} NMR (150 MHz, CD
3
OD) δ 153.7, 152.0,
9
4
6.4, 69.5, 60.8, 46.4, 32.7, 26.2, 23.6, 19.9, 18.8, -1.5, -
(
4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-cyclopropyl-
+
.6, -4.7 ppm; HRMS (ESI) m/z: [M+H] Calcd for
Si : 370.2228, found: 370.2232.
5
,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one
C
18
H
36NO
3
2
(
7i)
o
25
3-p-Tolyl-4a,5,6,7-tetrahydropyrrolo[1,2-c][1,3]oxazin-
-one (8a)
White solid (65 mg, 69%), mp 67-69 C; [α]
D
= -36.4 (c
3
.00, CHCl ); IR (film): νmax 2950, 2927, 2855, 1722, 1456,
-1 1
1
1
7
4
1
1
0
3
73 cm ; H NMR (400 MHz, CDCl ) δ 4.67-4.55 (m, 1H),
o
.37 (d, J = 13.2 Hz, 1H), 3.82-3.74 (m, 1H), 3.64-3.56 (m,
H), 2.73-2.62 (m, 1H), 2.09-1.94 (m, 1H), 1.88-1.80 (m,
H), 1.62-1.51 (m, 1H), 1.43-1.34 (m, 2H), 0.86 (s, 9H),
White solid (86 mg, 75%), mp 114-116 C; IR (film): νmax
-1 1
2543, 2080, 1637, 1435, 1211, 1079, 750 cm ; H NMR
3
(400 MHz, CDCl ) δ 7.56-7.49 (m, 2H), 7.20-7.14 (m,
.81-0.75 (m, 2H), 0.70-0.55 (m, 2H), 0.01 (s, 6H) ppm;
2H), 5.62 (d, J = 2.0 Hz, 1H), 4.23 (dd, J = 11.2, 3.6 Hz,
1H), 3.79-3.70 (m, 1H), 3.57-3.49 (m, 1H), 2.35 (s, 3H),
2.26-2.19 (m, 1H), 2.06-2.01 (m, 1H), 1.92-1.84 (m, 1H),
1
3
1
C{ H} NMR (150 MHz, CDCl
3
) δ 152.2, 150.9, 95.0,
6
8.1, 59.8, 45.5, 32.0, 25.8, 18.9, 18.0, 12.6, 4.5, 4.1, -4.6,
+
13
1
-
4.8 ppm; HRMS (ESI) m/z: [M+H] Calcd for
3
1.72-1.63 (m, 1H) ppm; C{ H} NMR (150 MHz, CDCl )
C
17
H
30NO
3
Si: 324.1990, found: 324.1988.
δ 149.9, 149.2, 139.5, 129.3, 129.1, 124.9, 97.5, 56.4, 45.9,
+
3
3.4, 22.2, 21.4 ppm; HRMS (ESI) m/z: [M+H] Calcd for
: 230.1176, found: 230.1173.
14 2
C H16NO
(
4aS,5S)-3-tert-Butyl-5-(tert-butyldimethylsilyloxy)-
,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one
7j)
5
(
General Procedure for Synthesis of 9b-9m. To a solution
of N,O-acetal 5c (100 mg, 1.0 eq.) and 6 (2.0 eq.) in
.
o
25
anhydrous DCM (1.5 mL) was treated with BF
3
OEt
2
(2.0
White solid (62 mg, 63%), mp 91-93 C; [α]
.25, CH OH); IR (film): νmax 2081, 1635, 1456, 1081, 697
cm ; H NMR (400 MHz, CD OD) δ 4.78 (d, J = 4.0 Hz,
D
= -26.0 (c
eq.) at -50°C under an argon atmosphere. After stirring for
0.5 h, the mixture was allowed to warm to room
temperature. The mixture was quenched with saturated
0
3
-
1 1
3
1
H), 4.25-4.19 (m, 1H), 3.89 (d, J = 4.0 Hz, 1H), 3.74-3.68
3
aqueous solution of NaHCO and extracted with EtOAc for
(
m, 1H), 2.80-2.71 (m, 1H), 2.01-1.88 (m, 1H), 1.86-1.78
m, 1H), 1.68-1.60 (m, 1H), 1.41-1.35 (m, 1H), 1.08 (s,
three times. The combined organic layers were washed
(
13
1
2 4
with brine and dried over anhydrous Na SO . Filtered and
9
H), 0.85 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H) ppm; C{ H}
concentrated under reduced pressure, the residue was
NMR (150 MHz, CDCl
3
) δ 159.3, 151.4, 93.6, 67.8, 59.7,
dissolved in anhydrous MeCN (1.5 mL), and treated with
4
5.2, 34.4, 32.1, 27.4, 25.9, 18.9, 18.1, 0.1, -4.5 ppm;
.
+
BF
3
OEt
2
(2.0 eq.) at room temperature under an argon
HRMS (ESI) m/z: [M+H] Calcd for C18
40.2303, found: 340.2304.
3
H34NO Si:
atmosphere for 1 h. Then the resulted mixture was
concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (PE/EA=3:1) to
give the compound 9b-9m.
3
(
4aS,5S)-5-(tert-Butyldimethylsilyloxy)-3-(pent-4-ynyl)-
,6,7,8-tetrahydropyrido[1,2-c][1,3]oxazin-1(4aH)-one
7k)
5
(
6
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201901141
o
25
(
4aS,5S)-5-Hydroxy-3-phenyl-4a,5,6,7-
White solid (43 mg, 54%), mp 150-152 C; [α]
0.50, CH OH); IR (film): νmax 3421, 2981, 2844, 1637,
491, 693 cm ; H NMR (400 MHz, CD
(m, 2H), 7.44-7.33 (m, 2H), 5.92-5.82 (m, 1H), 4.35-4.28
m, 1H), 4.27-4.20 (m, 1H), 3.82-3.71 (m, 1H), 3.52-3.43
(m, 1H), 2.15-2.02 (m, 1H), 1.96-1.88 (m, 1H) ppm;
D
= +4.2 (c
tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one (9b)
3
-
1 1
1
3
OD) δ 7.68-7.58
o
25
White solid (48 mg, 69%), mp 191-192 C; [α]
(
1
D
= +46.6
(
c 1.00, CH OH); IR (film): νmax 3446, 2065, 1634, 1495,
3
-
1 1
296, 543 cm ; H NMR (400 MHz, CDCl ) δ 7.68-7.62
3
13
1
C{ H} NMR (100 MHz, CD
3
OD) δ 152.2, 150.1, 136.2,
(
(
(
m, 2H), 7.41-7.35 (m, 3H), 5.87-5.81 (m, 1H), 4.13-4.03
m, 2H), 3.85-3.75 (m, 1H), 3.69-3.61 (m, 1H), 2.38-2.30
1
32.0, 129.8, 127.3, 97.7, 72.8, 63.2, 45.2, 32.2 ppm;
+
13
1
HRMS (ESI) m/z: [M+H] Calcd for C13
66.0579, found: 266.0578.
3
H13ClNO :
m, 1H), 2.22 (s, 1H), 1.92-1.82 (m, 1H) ppm; C{ H}
2
NMR (100 MHz, CDCl
3
) δ 149.7, 149.6, 131.7, 129.6,
1
28.7, 125.1, 96.2, 75.9, 61.5, 43.8, 31.2 ppm; HRMS
+
(
ESI) m/z: [M+H] Calcd for C13
H
14NO
3
: 232.0968, found:
(4aS,5S)-3-(2-Chlorophenyl)-5-hydroxy-4a,5,6,7-
tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one (9h)
2
32.0967.
o
25
(
4aS,5S)-5-Hydroxy-3-p-tolyl-4a,5,6,7-
White solid (39 mg, 49%), mp 160-162 C; [α]
(c 0.10, CH OH); IR (film): νmax 3448, 2920, 2849, 1637,
435, 1083, 617 cm ; H NMR (400 MHz, CD
7.55-7.51 (m, 1H), 7.47-7.39 (m, 1H), 7.37-7.31 (m, 2H),
.62 (d, J = 2.0 Hz, 1H), 4.32-4.30 (m, 1H), 4.30-4.28 (m,
1H), 3.82-3.78 (m, 1H), 3.51-3.45 (m, 1H), 2.14-2.07 (m,
D
= +13.0
tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one (9c)
3
-
1
1
1
3
OD) δ
o
25
White solid (53 mg, 72%), mp 182-184 C; [α]
D
= +51.6
5
(
c 0.25, CH OH); IR (film): νmax 3447, 2070, 1676, 1637,
3
-
1 1
1
3
444, 744 cm ; H NMR (500 MHz, CD OD) δ 7.57-7.53
13
1
1
H), 1.96-1.91 (m, 1H) ppm; C{ H} NMR (150 MHz,
CD OD) δ 152.3, 150.4, 149.6, 133.8, 133.2, 131.7 (d, J =
5.0 Hz), 131.3, 128.1, 102.9, 72.7, 63.2, 45.2, 32.2 ppm;
HRMS (ESI) m/z: [M+H] Calcd for C13
66.0579, found: 266.0580.
(
m, 2H), 7.25-7.20 (m, 2H), 5.95 (d, J = 1.0 Hz, 1H), 4.00-
.94 (m, 2H), 3.74-3.67 (m, 1H), 3.61-3.56 (m, 1H), 2.36
s, 3H), 2.30-2.24 (m, 1H), 1.86-1.79 (m, 1H) ppm;
3
3
1
(
+
1
3
1
3
H13ClNO :
3
C{ H} NMR (150 MHz, CD OD) δ 151.9, 150.4, 140.8,
2
1
30.3, 130.2, 125.7, 97.4, 76.2, 62.4, 44.7, 31.4, 21.3 ppm;
+
HRMS (ESI) m/z: [M+H] Calcd for C14
3
H16NO : 246.1125,
found: 246.1125.
(4aS,5S)-5-Hydroxy-3-(4-methoxyphenyl)-4a,5,6,7-
tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one (9i)
(
4aS,5S)-5-Hydroxy-3-m-tolyl-4a,5,6,7-
o
25
tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one (9d)
White solid (42 mg, 54%), mp 156-158 C; [α]
D
= +38.4
(
c 0.25, CH OH); IR (film): νmax 3325, 2919, 1084, 1514,
3
-
1 1
o
25
3
744 cm ; H NMR (400 MHz, CDCl ) δ 7.60-7.53 (m, 2H),
White solid (54 mg, 73%), mp 180-182 C; [α]
D
= +22.0
3
c 0.10, CH OH); IR (film): νmax 2919, 1714, 1473, 1083,
-1 1
6
.91-6.84 (m, 2H), 5.76-5.69 (m, 1H), 4.12-4.01 (m, 2H),
(
3.81 (s, 3H), 3.79-3.72 (m, 1H), 3.66-3.59 (m, 1H), 2.58 (s,
7
1
1
3
72 cm ; H NMR (500 MHz, CD OD) δ 7.53-7.50 (m,
13
1
1
H), 2.37-2.27 (m, 1H), 1.92-1.79 (m, 1H) ppm; C{ H}
H), 7.49-7.45 (m, 1H), 7.30-7.26 (m, 1H), 7.22-7.18 (m,
NMR (100 MHz, CDCl ) δ 160.7, 149.8, 149.4, 126.5,
3
H), 5.84 (d, J = 2.5 Hz, 1H), 4.37-4.34 (m, 1H), 4.30-4.27
1
24.2, 114.0, 94.5, 75.9, 61.5, 55.5, 43.8, 31.1 ppm;
(
m, 1H), 3.86-3.80 (m, 1H), 3.55-3.50 (m, 1H), 2.37 (s,
+
13
1
HRMS (ESI) m/z: [M+H] Calcd for C14
found: 262.1076.
4
H16NO : 262.1074,
3
H), 2.18-2.10 (m, 1H), 2.00-1.96 (m, 1H) ppm; C{ H}
OD) δ 151.9, 150.4, 139.5, 132.9,
31.2, 129.6, 126.2, 122.9, 98.1, 76.2, 62.4, 44.7, 31.3,
NMR (150 MHz, CD
3
1
2
C
+
1.4 ppm; HRMS (ESI) m/z: [M+H] Calcd for
: 246.1125, found: 246.1134.
(4aS,5S)-3-Hexyl-5-hydroxy-4a,5,6,7-
14
H
16NO
3
tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one (9j)
o
25
(
4aS,5S)-3-(4-Bromophenyl)-5-hydroxy-4a,5,6,7-
White solid (55 mg, 77%), mp 172-174 C; [α]
0.25, CH OH); IR (film): νmax 3387, 2926, 2852, 1715,
682, 1661, 1633 cm ; H NMR (400 MHz, CD
4.99-4.94 (m, 1H), 4.21-4.12 (m, 1H), 4.05-3.99 (m, 1H),
.74-3.66 (m, 1H), 3.40-3.33 (m, 1H), 2.15-2.10 (m, 2H),
2.03-1.96 (m, 1H), 1.91-1.82(m, 1H), 1.52-1.46 (m, 2H),
.35-1.28 (m, 3H), 1.26-1.16 (m, 3H), 0.87-0.83 (m, 3H)
D
= -2.0 (c
tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one (9e)
3
-
1
1
1
3
OD) δ
o
25
White solid (60 mg, 65%), mp 188-190 C; [α]
(
D
= +42.0
3
c 0.25, CH OH); IR (film): νmax 3421, 2076, 1637, 1491,
-1 1
3
6
5
3
2
3
97 cm ; H NMR (400 MHz, CDCl ) δ 7.53-7.48 (m, 4H),
1
.86-5.83 (m, 1H), 4.14-4.06 (m, 1H), 4.05-4.01 (m, 1H),
.85-3.74 (m, 1H), 3.68-3.60 (m, 1H), 2.40-2.30 (m, 1H),
13
1
ppm; C{ H} NMR (150 MHz, CD
96.4, 72.6, 62.7, 45.1, 33.3, 32.7, 32.0, 29.7, 27.2, 23.6,
4.4 ppm; HRMS (ESI) m/z: [M+H]+ Calcd for
: 240.1594, found: 240.1591.
3
OD) δ 154.2, 152.8,
1
3
1
.21 (d, J = 4.0 Hz, 1H), 1.92-1.80 (m, 1H) ppm; C{ H}
1
NMR (100 MHz, CDCl
3
) δ 149.3, 148.8, 131.9, 130.6,
13 3
C H22NO
1
26.6, 123.9, 96.7, 75.8, 61.5, 43.8, 31.2 ppm; HRMS
+
(
ESI) m/z: [M+H] Calcd for C13
3
H13BrNO : 310.0073,
found: 310.0074, 312.0076.
(4aS,5S)-3-tert-Butyl-5-hydroxy-4a,5,6,7-
tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one (9k)
(
4aS,5S)-3-(3-Bromophenyl)-5-hydroxy-4a,5,6,7-
o
25
tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one (9f)
White solid (48 mg, 76%), mp 140-142 C; [α]
.25, CH OH); IR (film): νmax 3422, 2077, 1637, 1033, 745
cm ; H NMR (400 MHz, CD OD) δ 5.05 (d, J = 2.0 Hz,
H), 4.26-4.18 (m, 1H), 4.08-4.04 (m, 1H), 3.77-3.69 (m,
1H), 3.45-3.38 (m, 1H), 2.10-2.01 (m, 1H), 1.93-1.86 (m,
D
= -26.8 (c
0
3
-
1 1
o
25
3
White solid (49 mg, 53%), mp 167-169 C; [α]
D
= +1.6 (c
1
0
1
.50, CH OH); IR (film): νmax 3446, 2065, 1635, 1398,
3
-
1 1
3
084, 568 cm ; H NMR (400 MHz, CD OD) δ 7.85-7.79
13
1
1
3
H), 1.14 (s, 9H) ppm; C{ H} NMR (150 MHz, CD OD)
(
(
m, 1H), 7.65-7.60 (m, 1H), 7.56-7.47 (m, 1H), 7.35-7.26
δ 161.4, 153.0, 93.8, 72.6, 62.6, 45.0, 35.5, 32.1, 27.7 ppm;
m, 1H), 5.90 (d, J = 1.6 Hz, 1H), 4.35-4.30 (m, 1H), 4.28-
+
HRMS (ESI) m/z: [M+H] Calcd for C11
found: 212.1280.
3
H18NO : 212.1281,
4
2
.24 (m, 1H), 3.82-3.74 (m, 1H), 3.52-3.44 (m, 1H), 2.14-
13 1
.05 (m, 1H), 1.96-1.90 (m, 1H) ppm; C{ H} NMR (150
OD) δ 152.0, 149.6, 135.4, 133.2, 131.4, 128.7
MHz, CD
3
(
d, J = 15.0 Hz), 124.5 (d, J = 15.0 Hz), 123.6, 98.5, 72.8,
(4aS,5S)-3-(Hex-5-ynyl)-5-hydroxy-4a,5,6,7-
tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one (9l)
+
6
3.2, 45.3, 32.2 ppm; HRMS (ESI) m/z: [M+H] Calcd for
: 310.0073, found: 310.0076, 312.0055.
C
13
H
13BrNO
3
25
Yellow oil (36 mg, 51%). [α]
D
= -14.2 (c 0.50, CH
3
OH);
(
4aS,5S)-3-(4-Chlorophenyl)-5-hydroxy-4a,5,6,7-
IR (film): νmax 3422, 2083, 1637, 1438, 1180, 1109, 713
-
1
1
tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one (9g)
cm ; H NMR (500 MHz, CD
3
OD) δ 5.08-5.04 (m, 1H),
4
3
1
.25-4.21 (m, 1H), 4.13-4.07 (m, 1H), 3.82-3.74 (m, 1H),
.47-3.42 (m, 1H), 2.26-2.20 (m, 6H), 2.11-2.04 (m, 1H),
.96-1.90 (m, 1H), 1.72-1.67 (m, 2H), 1.61-1.57 (m, 2H)
7
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201901141
1
3
1
ppm; C{ H} NMR (100 MHz, CD
3
OD) δ 153.8, 152.7,
examples, see: c) S. B. Jones, B. Simmons, A.
Mastracchio, D. W. C. MacMillan, Nature 2011, 475,
9
1
6.7, 84.7, 72.5, 69.7, 62.7, 45.1, 32.7, 32.0, 28.9, 26.3,
+
8.8 ppm; HRMS (ESI) m/z: [M+H] Calcd for
: 236.1281, found: 236.1281.
1
83; d) G. Yue, Y. Zhang, L. Fang, C.-C. Li, T. Luo, Z.
C
13
H
18NO
3
Yang, Angew. Chem. Int. Ed. 2014, 53, 1837; e) C. R.
Jamison, J. J. Badillo, J. M. Lipshultz, R. J. Comito, D.
W. C. MacMillan, Nat. Chem. 2017, 9, 1165; f) W. H.
So, C. T. T. Wong, J. Xia, Chin. Chem. Lett. 2018, 29,
(
4aS,5S)-5-Hydroxy-3-(pent-4-ynyl)-4a,5,6,7-
tetrahydropyrrolo[1,2-c][1,3]oxazin-1-one (9m)
2
5
Yellow oil (35 mg, 53%). [α]
D
= -9.2 (c 0.25, CH
3
OH);
1
058; g) X. Lu, S.-J. He, W.-M. Cheng, J. Shi, Chin.
IR (film): νmax 3447, 2976, 2548, 2237, 2074, 1715, 1649,
-
1
1
Chem. Lett. 2018, 29, 1001; h) Q. Gu, X. Wang, B. Sun,
G. Lin, Org. Lett. 2019, 21, 5082.
1
187, 752 cm ; H NMR (400 MHz, CD OD) δ 5.07-5.01
3
(
(
(
(
m, 1H), 4.22-4.17 (m, 1H), 4.08-4.04 (m, 1H), 3.78-3.70
m, 1H), 3.44-3.37 (m, 1H), 2.31-2.27 (m, 2H), 2.24-2.20
m, 3H), 2.09-2.00 (m, 1H), 1.92-1.85 (m, 1H), 1.76-1.70
[2] For books on pyridine alkaloids, see: a) S. W. Pelletier,
Ed., Alkaloids: Chemical and Biological Perspectives,
Wiley-Interscience, New York, 1985; b) S. W. Pelletier,
Ed., Alkaloids: Chemical and Biological Perspectives,
Pergamon, Oxford, 1996; For selected reviews, see: c)
P.-Q. Huang, Synlett, 2006, 1133; d) B. L. Stocker, E.
M. Dangerfield, A. L. Win-Mason, G. W. Haslett, M. S.
M. Timmer, Eur. J. Org. Chem., 2010, 1615; For
selected examples, see: e) J. Kim, J. S. Schneekloth, E.
J. Sorensen, Chem. Sci. 2012, 3, 2849; f) E.
Schütznerová, A. G. Oliver, A. Přibylka, V. Krchňák,
Adv. Synth. Catal. 2018, 360, 3693; g) R. Roldán, K.
Hernández, J. Joglar, J. Bujons, T. Parella, W.-D.
Fessner, P. Clapés, Adv. Synth. Catal. 2019, 361, 2673.
1
3
1
3
m, 2H) ppm; C{ H} NMR (150 MHz, CD OD) δ 153.2,
1
1
52.6, 97.1, 84.3, 72.5, 70.1, 62.7, 45.1, 32.2, 32.0, 26.3,
+
8.2 ppm; HRMS (ESI) m/z: [M+H] Calcd for
: 222.1125, found: 222.1123.
C
12
H
16NO
3
(
+)-Febrifugine (1)
The conversion of α-bromoketone 11 was achieved
through the following known processes: (i) Removal of
TMS group from 7m (3.21 g, 8.70 mmol), with KOH (2.92
[
21]
g, 52.2 mmol), gave crude amine, which was protected
as benzyl carbamate 10 (2.47 g, 70% for two steps); (ii)
Treatment of 10 (870 mg, 2.15 mmol) with TMSOTf (0.78
mL, 4.30 mmol) in the presence of N,N-
diisopropylethylamine (DIPEA) (0.75 mL, 4.52 mmol) and
followed by NBS (575 mg, 3.23 mmol) afforded α-
[
15]
bromoketone 11 (792 mg, 76%). Coupling 11 (413 mg,
0
.85 mmol) with 4-hydroxyquinazoline (137 mg, 0.94
[3] a) J. B. Koepfli, J. F. Mead, J. A. Brockman, Jr., J. Am.
Chem. Soc. 1947, 69, 1837; b) J. B. Koepfli, J. F. Mead,
J. A. Brockman, J Am Chem Soc. 1949, 71, 1048.
[
15]
mmol) gave protected Febrifugine 12 (288 mg, 62%).
To a methanol solution (2.5 mL) of 12 (280 mg, 0.51
mmol) was added 6 M HCl (2.5 mL) and refluxed for 4 h.
After evaporating of the solvent, the residue was added
EtOH (5 mL) and refluxed for another 1 h. The mixture
was cooled to room temperature, basified to pH 9 by
addition of NaOH and extracted with DCM. The combined
[
4] a) A. Ishih, T. Miyase, T. Suzuki, F. W. Muregi, M.
Terada, J. Nat. Med. 2007, 61, 213; b) A. T. Khalil, F.-
R. Chang, Y.-H. Lee, C.-Y. Chen, C.-C. Liaw, P.
Ramesh, S.-S. F. Yuan, Y.-C. Wu, Arch. Pharm. Res.
organic layers were dried over anhydrous Na
CO
purified by silica gel flash chromatography (DCM/CH
2
SO
4
and
K
2
3
, filtered and concentrated. The crude product was
2
003, 26, 15; c) F. Ablondi, S. Gordon, J. Morton, J. H.
3
OH
Williams, J. Org. Chem. 1952, 17, 14.
=
10:1) to afford the compound 1 as a white solid (104 mg,
o
[11a]
o
25
6
8%), {mp 124-126 C; lit.
mp 133-136 C; [α]
D
=
[
11a]
20
[5] a) S. S. Bhupesh, G. S. Mugdha, Med. Chem. 2009, 5,
293; b) M. R. Linder, A. R. Heckeroth, M. Najdrowski,
A. Daugschies, D. Schollmeyer, C. Miculka, Bioorg.
Med. Chem. Lett. 2007, 17, 4140; c) S. Uesato, Y.
Kuroda, M. Kato, Y. Fujiwara, Y. Hase, T. Fujita,
Chem. Pharm. Bull. 1998, 46, 1.
+
20.4 (c 0.25, EtOH), lit.
[α]
D
= +14.0 (c 0.50, EtOH);
[
11d]
27
1
lit.
[α]
D
= +26.6 (c 0.1, EtOH)}; H NMR (500 MHz,
6
) δ 8.19-8.17 (m, 1H), 8.15-8.12 (m, 1H), 7.88-
DMSO-d
7
.83 (m, 1H), 7.72-7.68 (m, 1H), 7.59-7.54 (m, 1H), 5.01
(
d, J = 18.0 Hz, 1H), 4.96 (d, J = 18.0 Hz, 1H), 4.78 (d, J =
5
2
.5 Hz, 1H), 3.01-2.95 (m, 2H), 2.81-2.77 (m, 1H), 2.68-
.63 (m, 1H), 2.47-2.42 (m, 1H), 2.40-2.34 (m, 1H), 2.11
(
(
s, 1H), 1.92-1.87 (m, 1H), 1.59-1.50 (m, 1H), 1.39-1.31
13 1
m, 1H), 1.26-1.17 (m, 1H) ppm; C{ H} NMR (125 MHz, [6] a) A. Hameed, M. Al-Rashida, M. Uroos, S. A. Ali,
DMSO-d
6
) δ 203.9, 160.0, 148.1, 148.0, 134.5, 127.3,
Arshia, M. Ishtiaq, K. M. Khan, Expert Opin. Ther. Pat.
2018, 28, 281; b) M. Pines, I. Spector, Molecules 2015,
20.
1
27.2, 126.1, 121.4, 70.8, 60.1, 54.7, 45.6, 43.7, 34.2, 25.8
+
ppm; HRMS (ESI) m/z: [M+H] Calcd for C16
02.1499, found: 302.1501.
20 3 3
H N O :
3
[
7] a) G. Wellner, S. Mordechay, P. Evans, O. Genin, M.
Pines, O. Halevy, Histol. Histopathol. 2019, 34, 791; b)
D. G. Song, D. Kim, J. W. Jung, S. H. Nam, J. E. Kim,
H. J. Kim, J. H. Kim, S. J. Lee, C. H. Pan, S. Kim, J. W.
Lee, Faseb. J. 2019, 33, 4341; c) K. Y. Elahi-Gedwillo,
M. Carlson, J. Zettervall, P. P. Provenzano, Cancer Res.
Acknowledgements
We thank the National Natural Science Foundation of China
21772027 to B.-G. Wei) and (21702032 to C.-M. Si) and the
(
Open Research Fund Program of Beijing Key Lab of Plant
Resource Research and Development, BTBU (No. PRRD-2018-
ZD1) for financial support. The authors also thank Dr Han-Qing
Dong (Arvinas, Inc.) for helpful suggestions.
2
019, 79, 372; d) M. Pines, O. Levi, O. Genin, A. Lavy,
C. Angelini, V. Allamand, O. Halevy, Am. J. Pathol.
017, 187, 654.
2
[
[
8] Y. Luo, X. Y. Xie, D. Luo, Y. Wang, Y. J. Gao, J.
Leukocyte Biol. 2017, 102, 1333.
References
9] a) H. Huang, R. A. Brekken, Cancer Res. 2019, 79,
[
1] a) I. Ojima, Catalytic Asymmetric Synthesis, Wiley-
VCH: Weinheim, 2000; b) J. Tsuji, Transition Metal
Reagents and Catalysts: Innovations in Organic
Synthesis, Wiley: Chichester, 2000. For recent selected
3
28; b) L. H. Luo, Y. Gao, C. Yang, Z. W. Shao, X. H.
Wu, S. Li, L. M. Xiong, C. Chen, Biomed.
Pharmacother. 2018, 101, 745; c) T. L. Keller, D.
8
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201901141
Zocco, M. S. Sundrud, M. Hendrick, M. Edenius, J.
[15] R.-C. Liu, W. Huang, J.-Y. Ma, B.-G. Wei, G.-Q. Lin,
Yum, Y. J. Kim, H. K. Lee, J. F. Cortese, D. F. Wirth, J.
D. Dignam, A. Rao, C. Y. Yeo, R. Mazitschek, M.
Whitman, Nat. Chem. Biol. 2012, 8, 311.
Tetrahedron Lett. 2009, 50, 4046.
[
16] For recent selected reviews and examples: a) T.-D.
Tan, Y.-B. Chen, X.-Y. Fan, L.-W. Ye, Synlett 2019,
DOI: 10.1055/s-0037-1611903; b) X. Huang, S. Ma,
Acc. Chem. Res. 2019, 52, 1301; c) J. Guo, H. Wang, S.
Xing, X. Hong, Z. Lu, Chem 2019, 5, 881-; d) A. Hazra,
J. Chen, G. Lalic, J. Am. Chem. Soc. 2019, 141, 12464;
e) M. Osano, T. Kida, K. Yonekura, T. Tsuchimoto,
Adv. Synth. Catal. 2019, 361, 2736; f) J. Li, Y. Li, Z.
Wang, Y. Bian, S. Bai, L. Liu, J. Sun, J. Org. Chem.
2018, 83, 4257.
[
10] a) W. B. Mu, B. Y. Xu, H. R. Ma, J. Li, B. C. Ji, Z. D.
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9
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Advanced Synthesis & Catalysis
10.1002/adsc.201901141
FULL PAPER
Stereoselective Intermolecular [4+2] Process of
N,O-acetals with Terminal Alkynes for
Construction of Functional cis-Pyrido and
Pyrrolo[1,2-c][1,3]oxazin-1-ones
X
X
OH
N
O
R
H
n
O
n
.
BF3 Et O
N
2
N
O
N
N
Adv. Synth. Catal. Year, Volume, Page – Page
dr up to 99:1
H
Boc
O
O
R
X = H or TBS; n=0, 1; R = Alkyl, aryl
(+)-Febrifugine
a
a
a
Chen Wang, Zhuo-Ya Mao, Yi-Wen Liu, Qiao-E
b
a,
a,
Wang, Chang-Mei Si, * Bang-Guo Wei * and
Guo-Qiang Linc
1
0
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