Stereoselective total synthesis of (+)-radicamine B via anti,syn,syn-oxazine

Article abstract of DOI:10.1016/j.tetasy.2016.01.009

The stereoselective total synthesis of (+)-radicamine B was achieved using commercially available D-4-hydroxy-phenylglycine via chiral 1,3-oxazine, which has been applied to synthesis of amino polyols such as DAB-1, D-fagomine, and phytosphingosines. The key steps in this strategy were the palladium(0)-catalyzed stereoselective intramolecular oxazine formation, an extension of the chirality of anti,syn-oxazine with Lewis acid and vinylmagnesium bromide, and pyrrolidine ring formation via hydrogenation reaction. The chiral extension is also applicable to other chiral 1,3-oxazine derived from D-4-hydroxy-phenylglycine.

Full text of DOI:10.1016/j.tetasy.2016.01.009

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective total synthesis of (+)-radicamine B via
anti,syn,syn-oxazine
Jin-Seok Kim y, Gun-Woo Kim y, Jong-Cheol Kang, In-Soo Myeong, Changyoung Jung, Yong-Taek Lee,
⇑
Gyung-Ho Choo, Seok-Hwi Park, Gyu-Jin Lee, Won-Hun Ham
School of Pharmacy, Sungkyunkwan University, 16419, Seobu-ro 2066, Suwon-si, Gyeonggi-do, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective total synthesis of (+)-radicamine B was achieved using commercially available
Received 23 November 2015
Accepted 6 January 2016
Available online xxxx
D-4-hydroxy-phenylglycine via chiral 1,3-oxazine, which has been applied to synthesis of amino polyols
such as DAB-1, -fagomine, and phytosphingosines. The key steps in this strategy were the palladium(0)-
D
catalyzed stereoselective intramolecular oxazine formation, an extension of the chirality of anti,syn-oxazine
with Lewis acid and vinylmagnesium bromide, and pyrrolidine ring formation via hydrogenation
reaction. The chiral extension is also applicable to other chiral 1,3-oxazine derived from
D-4-hydroxy-phenylglycine.
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
HO
OH
HO
OH
OMe
OH
HO
HO
Several structurally related polyhydroxylated pyrrolidines have
been reported to be biologically active as antiviral agents,
acaricides, and competitive inhibitors of glycosidases (Fig. 1).1
(+)-Radicamine A 12 and (+)-radicamine B 23 were extracted from
Lobelia chinensis Lour, which was used as a diuretic, antidote, hemo-
stat, and carcinostatic agent for stomach cancer in Chinese folk
medicine.2c,4 Their relative configurations are similar to those of
(ꢀ)-codonopsine (3)5 and (ꢀ)-codonopsinine 4;5 accordingly, their
absolute configuration was proposed both to be (2S,3S,4S,5S). After
the first synthesis of radicamines by Yu and Huang, the absolute
configurations were revised to be (2R,3R,4R,5R).3j Cheng et al.
described the biological effects of radicamine B 2 and related
polyhydroxylated pyrrolidine derivatives.2a (ꢀ)-Codonopsine (3)
N
H
N
H
OH
(+)-radicamine A 1
HO OH
(+)-radicamine B 2
HO OH
OMe
Me
Me
N
N
Me
Me
OMe
OMe
(−)-codonopsine 3
(−)-codonopsinine 4
Figure 1. Chemical structures of (+)-radicamines, A 1, B 2, (ꢀ)-codonopsine 3, and
(ꢀ)-codonopsinine 4.
and (ꢀ)-codonopsinine
4 were extracted from Codonopsis
application in the total syntheses of (ꢀ)-conduramine F-1,8a
(+)-hyacinthacine A2,8b (ꢀ)-sphingofungin B,8b (+)-1-deoxyno-
jirimycin,8c and (+)-DMDP.8c In order to expand the synthetic
utility of chiral anti,syn,syn-oxazine derived from various amino
acids, we herein describe the stereoselective total synthesis of
clematidea, which show hypotensive pharmacological efficacy
without causing any effect on the central nervous system in
animals.6 Due to their biological activities and structures, which
include four contiguous stereocenters, many synthetic routes to
these molecules have been reported over the last decade.2,3,5
We have previously described the syntheses of chiral natural
(+)-radicamine
B 2 using anti,syn,syn-oxazine derived from
-4-hydroxy-phenylglycine (Fig. 2).
D
aminopolyols, such as DAB-1,
D-fagomine, phytosphingosines, and
daunosamine.7 Recently we developed a novel chiral building block,
2. Results and discussion
anti,syn,syn-oxazine derived from
D-serine and reported its
The retrosynthetic analysis shown in Scheme 1 indicates that
(+)-radicamine B 2 could be obtained by deprotection of pyrro-
lidine 5, which could be generated from anti,syn,syn-oxazine 6.
⇑
Corresponding author.
E-mail address: whham@skku.edu (W.-H. Ham).
Both authors contributed equally to this work.
y
http://dx.doi.org/10.1016/j.tetasy.2016.01.009
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kim, J.-S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.01.009

2
J.-S. Kim et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
OTBS
TBSO
OH
TBSO
N
OH
i) O3, MeOH
TBSO
TBSO
TBSO
N
O
N
O
O
ii) Method A or
Method B
Ph
Ph
anti,syn,syn-oxazine
Ph
anti,syn,anti-oxazine
anti,syn-oxazine
Method A : ZnCl2,
Method B :
, 0 oC, 64% dr. 10 : 1
MgBr
, 0 oC, 85%, dr. > 20 : 1
Zn
2
Figure 2. Previous report of chiral extension of anti,syn-oxazine derived from D-serine.
MeO
TBSO
OH
HO
OH
HO
OTBS
hydrogenation
ring cyclization
HO
HO
N
O
N
H
N
H
OH
OMe
Ph
5
(+)-radicamine B 2
6
MeO
OTBS
MeO
HO
OH
O
oxazine ring
cyclization
stereoselective
vinyl addition
Cl
OH
N
O
NHBz
NH2
D-4-hydroxy-phenylglycine
Ph
8
7
Scheme 1. Retrosynthetic analysis for (+)-radicamine B 2.
anti,syn,syn-Oxazine 6 could in turn be prepared from anti,syn-oxa-
zine 7 via stereoselective nucleophilic addition. The key intermedi-
ates, anti,syn-oxazine 7, could be achieved from anti-amino alcohol
8, which could be obtained from commercially available
To increase the stereogenic centers of anti,syn-oxazine 7, vari-
ous conditions were explored (Table 1). Ozonolysis of the pendant
olefin gave the corresponding aldehyde, which was subsequently
reacted with vinylmagnesium bromide in the absence of Lewis acid
to give the adduct anti,syn,syn-oxazine 6 with low diastereoselec-
tivity (1.6:1 mixture of syn/anti isomers at 0 °C and 1:1 mixture
at ꢀ78 °C; entries 1 and 7). Divinylzinc was also tested but unex-
pectedly gave low selectivity (entry 2).8b After extensive
screening of reaction conditions, we established that the reaction
of the aldehyde, ZnCl2, and vinylmagnesium bromide in a 1:1:3
D-4-hydroxy-phenylglycine.
The preparation of anti,syn-oxazine
7 from D-4-hydroxy-
phenylglycine is shown in Scheme 2. The Weinreb amide 9 was
obtained by successive esterification, benzoyl protection of amino
group, O-methylation of the phenolic OH, and Weinreb amide for-
mation using MeHNOMeꢁHCl, AlMe3 in CH2Cl2. Treatment of Wein-
reb amide 9 with vinyltin 10 and MeLiꢁLiBr complex solution in
ratio
delivered
anti,syn,syn-oxazine
6
with
good
THF at ꢀ78 °C gave
a,b-unsaturated ketone 11 in 86% yield.
diastereoselectivity in good yield (entries 3 and 8). In entries 4
and 9, it is interesting to note that moderate anti-selectivity was
obtained via the reaction with TiCl4. We also found that SnCl4
and BF3ꢁOEt2 gave low selectivities (entries 5, 6, 10, and 11). A
low temperature led to improved diastereomeric ratios but gave
low yields.
Chelation controlled hydride reduction of amino ketone 11 with
LiAlH(t-OBu)3 in EtOH at ꢀ78 °C, gave anti-amino alcohol 8 in
90% yield with excellent stereoselectivity (ds. >90%, as determined
by 1H NMR). Protection of anti-amino alcohol 8 with TBSCl in DMF
and subsequent oxazine ring cyclization with Pd(0) cat. afforded
anti,syn-oxazine 7 in good yield and with excellent diastereoselec-
tivity (75% and ds. >97% as determined by 1H NMR).
The total synthesis of (+)-radicamine B 2 is shown in Scheme 3.
After mesylation of anti,syn,syn-oxazine 6, subsequent ozonolysis
MeO
HO
O
O
e
a-d
OMe
N
OH
Bu3Sn
MeO
Cl
Me
NHBz
NH2
10
9
D
-4-hydroxy-phenylglycine
OTBS
O
MeO
MeO
OH
O
f
g,i
Cl
Cl
N
NHBz
NHBz
Ph
7
11
8
Reagents and conditions: (a) SOCl2, MeOH, reflux; (b) BzCl, Et3N, MeOH, 0 oC; (c) K2CO3, MeI, DMF; (d) MeNHOMe.HCl,
.
AlMe3, CH2Cl2, 82% over four steps; (e) , MeLi LiBr, −78 oC, 86%; (f) LiAlH(tBuO)3, EtOH, −78 oC, 90%, ds. >90%; (g)
10
TBSCl, imidazole, DMF, 93%; (i) Pd(PPh3)4, TBAI, NaH, THF, 0 oC, 75%, ds. >97%
Scheme 2. Preparation of anti,syn-oxazine 7 from D-4-hydroxy-phenylglycine.
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J.-S. Kim et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 1
anti,syn,syn-Oxazine 6 formation from anti,syn-oxazine 7
MeO
MeO
MeO
OTBS
TBSO
N
OH
TBSO
N
OH
1) O3, MeOH
2) Lewis acid,
MgBr
N
O
O
O
, THF,
Ph
Ph
Ph
temperature
anti,syn,anti-oxazine
6'
anti,syn-oxazine
7
anti,syn,syn-oxazine
6
Entry
Temp (°C)
Lewis acid
Ratio (6/60)a,b
Yieldc (%)
1
0
0
0
0
0
N/A
N/A
1.6:1
1:1
8:1
54
—
2d
3
ZnCl2
TiCl4
BF3OEt2
SnCl4
N/A
ZnCl2
TiCl4
BF3OEt2
SnCl4
83
48
55
48
60
64
50
45
45
4
5
6
7
8
9
10
11
1:3
1.2:1
1.1:1
1:1
8.5:1
1:3.5
1:1
0
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
1:2
a
Ratio was determined by 1H NMR.
b
The relative stereochemistry was established on the basis of the Rf value of the TLC analysis and comparison with 1H and 13C NMR of anti,syn,syn-oxazine and anti,syn,anti-
oxazine in Ref. 8a.
c
Two-step yield was indicated.
Divinylzinc was employed instead of vinylmagnesium bromide.
d
MeO
MeO
TBSO
N
OH
TBSO
N
OMs
HO
HO
OTBS
OH
OH
a
b
c
HO
HO
N
H
N
H
O
O
OMe
OH
Ph
Ph
12
6
5
(+)-radicamine B 2
Reagents and Conditions : (a) i) MsCl, Et3N, CH2Cl2, 98.6%; ii) O3, MeOH, −78 oC, then NaBH4, 82%; (b) Pd(OH)2, H2, MeOH/AcOH(9:1), 78%; (c) BBr3, CH2Cl2, 80%
Scheme 3. Stereoselective total synthesis of (+)-radicamine B 2.
and hydride reduction afforded the corresponding primary alcohol
12. Hydrogenolysis of resulting alcohol 12 with Pd(OH)2 and H2 in
the presence of methanol and acetic acid afforded pyrrolidine
derivative 5. Under these conditions, cyclization of the mesylate
formed pyrrolidine ring 5 as a single isomer as well as cleavage
of the oxazine ring. Finally, treatment of 5 with boron tribromide
afforded 2ꢁHBr. All spectroscopic data were similar to those
reported for 2ꢁHCl except for the specific rotation.3f,9 To confirm
the identity of 2ꢁHBr, the product was purified by ion-exchange
chromatography through Dowex 50WX8 (H+) to give (+)-radicamine
4. Experimental
4.1. General
Optical rotations were measured using a polarimeter in the sol-
vent specified. 1H and 13C NMR spectroscopic data were recorded a
500/125, or 700/175 MHz FT-NMR spectrometer, respectively. The
chemical shift values are reported in parts per million relative to
TMS or CDCl3 as the internal standards, and the coupling constants
are reported in Hertz. [a]
D values are given in 10ꢀ1 deg cm2 gꢀ1. IR
B 2. The specific rotation of synthetic 2, [a]
19 = +42.8 (c 0.04,
D
spectra were measured using an FT-IR spectrometer. Mass spectro-
scopic data were obtained using a Jeol JMS 700 high resolution
mass spectrometer with a magnetic sector–electric sector double
focusing analyser. Flash chromatography was carried out using
mixtures of ethyl acetate and hexane as the eluents. Unless other-
wise noted, all non-aqueous reactions were carried out under an
argon atmosphere using commercial grade reagents and solvents.
Tetrahydrofuran (THF) was distilled from sodium and benzophe-
none ketyl (indicator). Dichloromethane (CH2Cl2) was distilled
from calcium hydride.
MeOH),9 is similar to the reported value, [ 20 = +48.1 (c 0.34,
a]
D
EtOH),3b which confirms the identity of the absolute
configuration. Thus, (+)-radicamine B 2 was synthesized from
anti,syn,syn-oxazine 6 in 40.6% yield over four steps and from
D
-4-hydroxy-phenylglycine in 18.6% yield over 12 steps.
3. Conclusion
We have demonstrated that (+)-radicamine B 2 could be readily
obtained from homochiral anti,syn,syn-oxazine 6 derived from D-4-
4.2. (R)-N-(2-(Methoxy(methyl)amino)-1-(4-methoxyphenyl)-2-
oxoethyl) benzamide 9
hydroxy-phenylglycine. The key features in this strategy were
stereoselective intramolecular oxazine formation, stereoselective
addition of vinylmagnesium bromide in the presence of a Lewis
acid, and cyclization by catalytic hydrogenolysis of oxazine. It is
important to note that we controlled the fourth stereocenter with
high stereoselectivity via Lewis acid mediated nucleophilic
addition.
To a solution of N,O-dimethyl-hydroxylamine hydrochloride
(4.19 g, 42.92 mmol) in CH2Cl2 (51 mL) was added trimethylalu-
minum (21.46 mL of a 2.0 M solution in hexane, 42.92 mmol) at
0 °C (Caution: CH4 evolution). The mixture was stirred for 30 min
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4
J.-S. Kim et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
at room temperature. Subsequently, a solution of methyl ester
(4.28 g, 14.31 mmol) in CH2Cl2 (21 mL) was added dropwise. The
mixture was stirred at room temperature for 1 h, after which time
TLC analysis indicated complete reaction. The reaction mixture was
cooled to 0 °C and carefully quenched with 10% sodium potassium
tartrate. After being stirred for 1 h at room temperature, the result-
ing suspension was filtered through a Celite pad and washed with
CH2Cl2. The filtrate was concentrated in vacuo to give the crude
product, which upon purification by column chromatography on
silica gel gave the Weinreb amide 9 (4.23 g, 90% yield) as a color-
114.39, 124.18, 127.25, 128.87, 131.98, 131.99, 133.24, 133.26,
134.37, 134.38, 134.40, 159.59, 167.72; HRMS (FAB) calcd for
C19H21ClNO3 346.1210, found 346.1210.
4.5. N-((1R,2S,E)-2-(tert-Butyldimethylsilyloxy)-5-chloro-1-(4-
methoxyphenyl)pent-3-enyl)benzamide
Imidazole (1.02 g, 14.96 mmol) and tert-butyldimethylchlorosi-
lane (3.01 g, 19.95 mmol) were added to a stirred solution of anti-
amino alcohol 8 (3.45 g, 9.98 mmol) in DMF (6.9 mL) at room tem-
perature, after which stirring was continued for 2 h. The reaction
mixture was quenched with H2O and then extracted twice with
EtOAc. The organic layer was washed with brine, dried over MgSO4,
and evaporated in vacuo. Purification by silica gel chromatography
less oil; [
a]
25 = ꢀ115.30 (c 0.1, CHCl3); IR (neat) mmax 3327, 1644,
D
1585, 1514, 1484, 1391, 1309,1253, 1182, 1033, 996 cmꢀ1
;
1H
NMR (500 MHz, CDCl3) d 3.22 (s, 3H), 3.50 (s, 3H), 3.79 (s, 3H),
6.13 (d, J = 6.5 Hz, 1H), 6.88 (m, 2H), 7.39–7.49 (m, 5H), 7.80 (m,
2H); 13C NMR (125 MHz, CDCl3) d 31.12, 53.85, 55.50, 61.46,
76.66, 114.45, 127.36, 128.70, 129.44, 131.81, 134.31, 159.71,
gave TBS ether (4.2 g, 9.13 mmol, 93%); [
IR (neat)
a
]
25 = ꢀ46.9 (c 0.1, CHCl3);
D
m
max: 3432, 3298, 2955, 2933, 2899, 2858, 1637, 1540,
166.47; HRMS (FAB) calcd for
329.1501.
C
18H21N2O4 329.1501, found
1514, 1491, 1465, 1447, 1309, 1249, 1182, 1115, 1082, 1033,
974, 873, 836, 780, 698, 672 cmꢀ1 1H NMR (500 MHz, CDCl3) d
;
0.04 (s, 3H), 0.05 (s, 3H), 0.92 (s, 9H), 3.80 (s, 3H), 3.98 (m, 2H),
4.62 (m, 1H), 5.13 (td, J = 8.0, 4.0 Hz, 1H), 5.53 (m, 1H), 5.88 (m,
1H), 6.72 (d, J = 8.0 Hz, 1H), 6.86 (m, 2H), 7.28 (m, 2H), 7.41-7.51
(m, 3H), 7.77 (m, 2H); 13C NMR (125 MHz, CDCl3) d ꢀ4.74, ꢀ4.04,
18.35, 26.05, 30.80, 44.24, 55.48, 58.00, 74.93, 76.67, 113.97,
127.07, 128.52, 128.81, 129.30, 130.56, 131.72, 134.43, 134.80,
159.29, 166.67; HRMS (FAB) calcd for C25H35ClNO3Si 460.2075,
found 460.2073.
4.3. (R,E)-N-(5-Chloro-1-(4-methoxyphenyl)-2-oxopent-3-enyl)
benzamide 11
Vinyltin 10 (14.17 g, 38.65 mmol) was dissolved in dry THF
(90 mL) and cooled to ꢀ78 °C. Next, 1.5 M MeLiꢁLiBr in hexane
(25.76 mL, 38.65 mmol) was added dropwise. The mixture was
stirred for 30 min at the same temperature. Subsequently, a solu-
tion of Weinreb amide 9 (4.23 g, 12.88 mmol) in dry THF (40 mL)
was added dropwise and stirring was continued for 30 min, after
which time TLC analysis indicated complete reaction. The reaction
was quenched by aqueous sat. NH4Cl, and then warmed to room
temperature. The layers were separated and the aqueous layer
was extracted with ethyl acetate. The combined organic layer
was concentrated in vacuo. The resulting substance was purified
by silica gel column chromatography and gave amino ketone 11
4.6.
(4R,5R,6R)-5-(tert-Butyldimethylsilyloxy)-4-(4-methoxy-
phenyl)-2-phenyl-6-vinyl-5,6-dihydro-4H-1,3-oxazine 7
At first, NaH (55% in mineral oil, 430 mg, 18.26 mmol) and n-
Bu4NI (3.38 g, 9.13 mmol) were added to a stirred solution of allyl
chloride (4.20 g, 9.13 mmol) in anhydrous THF (450 mL) at 0 °C.
After stirring for 5 min, Pd(PPh3)4 (2.11 g, 1.83 mmol) was added
to the mixture and stirring was continued for 12 h at the same
temperature. The reaction mixture was filtered through a pad of
silica and then evaporated under reduced pressure to give a crude
product. Purification of this material by silica gel chromatography
(hexanes/EtOAc = 30/1) gave 7 (2.90 g, 6.846 mmol, 75% yield);
(3.81 g, 11.08 mmol, 86% yield); [
(neat)
a
]
25 = ꢀ191.7 (c 0.1, CHCl3): IR
D
m
max: 3394, 3063, 3003, 2959, 2933, 2840, 1711, 1640,
1607, 1581, 1514, 1484, 1424, 1346, 1305, 1253, 1179, 1115,
1033, 978, 836, 717 cmꢀ1 1H NMR (500 MHz, CDCl3) d 3.80 (s,
;
1H), 4.12 (dd, J = 6.0, 1.5 Hz, 2H), 5.87 (d, J = 6.0 Hz, 1H), 6.41 (td,
J = 15.5, 1.5 Hz, 1H), 6.91 (m, 2H), 7.02 (td, J = 15.0, 6.0 Hz, 1H),
7.32 (m, 2H), 7.41–7.50 (m, 3H), 7.52 (d, J = 6.5, 1H), 7.82 (m,
2H); 13C NMR (125 MHz, CDCl3) d 31.12, 42.82, 55.53, 61.99,
76.68, 115.04, 127.36, 127.97, 128.78, 129.99, 131.97, 134.08,
142.10, 160.19, 166.58, 194.06; HRMS (FAB) calcd for C19H19ClNO3
344.1053, found 344.1053.
[
a
]
25 = ꢀ8.0 (c 0.1, CHCl3); IR (neat) mmax 2955, 2929, 2858, 1659,
D
1614, 1585, 1514, 1465, 1365, 1324, 1302, 1283, 1249, 1179,
1115, 1074, 1037, 1011, 996, 929, 870, 836, 780, 702, 668 cmꢀ1
;
1H NMR (500 MHz, CDCl3) d ꢀ0.22 (s, 3H), ꢀ0.03 (s, 3H), 0.87 (s,
3H), 3.83 (s, 3H), 3.84 (dd, J = 6.5, 4.0 Hz, 1H), 4.51 (d, J = 6.5 Hz,
1H), 4.73 (ddd, J = 6.5, 4.0, 1.5 Hz, 1H), 5.35 (d, J = 1.5 Hz, 1H),
5.38 (dt, J = 6.5, 1.5 Hz, 1H), 6.11 (ddd, J = 8.5, 5.25, 4.5 Hz, 1H),
6.90 (m, 2H), 7.21 (m, 2H), 7.40-7.49 (m, 3H), 8.09 (m, 2H); 13C
NMR (125 MHz, CDCl3) d ꢀ5.01, ꢀ4.62, 18.22, 25.96, 55.57, 61.04,
71.41, 75.65, 113.94, 117.76, 127.75, 128.28, 129.24, 130.77,
133.40, 134.25, 154.16, 159.12; HRMS (FAB) calcd for C25H34NO3Si
424.2308, found 424.2306.
4.4. N-((1R,2S,E)-5-Chloro-2-hydroxy-1-(4-methoxyphenyl)pent-3-
enyl) benzamide 8
To a solution of amino ketone 11 (3.81 g, 11.08 mmol) in etha-
nol (110 mL) was added lithium tri-tert-butoxyaluminohydride
(1.0 M solution in THF, 27.71 mL, 27.71 mmol) at ꢀ78 °C. After
the reaction mixture was stirred at the same temperature for 2 h,
a 10% aqueous solution of citric acid was added. The resulting mix-
ture was warmed to room temperature and extracted with ethyl
acetate. The organic layers were combined, washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo to give crude
products. Column chromatography on silica gel gave anti-amino
4.7.
(S)-1-((4R,5R,6R)-5-(tert-Butyldimethylsilyloxy)-4-(4-
methoxyphenyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazin-6-yl)prop-
2-en-1-ol 6
anti,syn-Oxazine 7 (2.90 g, 6.846 mmol) was dissolved in dry
methanol (103 mL) and cooled to ꢀ78 °C. Ozone was then passed
through the solution until the reaction was complete. The reaction
mixture was quenched with (CH3)2S (5.0 mL, 68.46 mmol) and
allowed to warm to room temperature. The solvents were evapo-
rated under reduced pressure. The crude aldehyde was immedi-
ately employed in the next step without further purification.
Next, ZnCl2 (1.0 M solution in diethyl ether; 6.85 mL, 6.85 mmol)
and vinylmagnesium bromide (1.0 M solution in THF; 34.23 mL,
34.23 mmol) were added to a solution of the aldehyde in THF
alcohol 8 (3.45 g, 9.98 mmol, 90% yield); [
a
]
25 = ꢀ45.7 (c 0.1,
D
CHCl3); IR (neat)
mmax: 3309, 3003, 2936, 2836, 1633, 1585, 1532,
1518, 1491, 1465, 1447, 1313, 1283, 1249, 1182, 1119, 1082,
1033, 970, 836 cmꢀ1 1H NMR (500 MHz, CDCl3) d 3.81 (s, 1H),
;
4.02 (dd J = 6.0, 1.0 Hz, 2H), 4.58 (m, 1H), 5.27 (dd, J = 6.0, 3.5 Hz,
1H), 5.75 (td, J = 6.0, 1.0 Hz, 1H), 5.92 (m, 1H), 6.75 (d, J = 7.5, Hz,
1H), 6.90 (m, 2H), 7.29 (m, 2H), 7.43–7.54 (m, 3H), 7.79 (m, 2H);
13C NMR (125 MHz, CDCl3) d 31.13, 44.23, 55.53, 58.47, 74.77,
Please cite this article in press as: Kim, J.-S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.01.009

J.-S. Kim et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
(145 mL) at ꢀ78 °C over 12 h. The reaction was quenched by a sat-
urated aqueous solution of NH4Cl and then warmed to room tem-
perature. The organic layer was separated, and the aqueous layer
was extracted with ethyl acetate. The combined organic layer
was washed with saturated NaHCO3 solution and brine, dried over
MgSO4, and filtered. The filtrate was concentrated in vacuo. The
resulting substance was purified by silica gel column chromatogra-
4.10.
(S)-1-((4R,5R,6S)-5-(tert-Butyldimethylsilyloxy)-4-(4-
methoxyphenyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazin-6-yl)-2-
hydroxyethyl methanesulfonate 12
Mesylate (0.36 g, 0.677 mmol) was dissolved in dry methanol
(27 mL) and cooled to ꢀ78 °C. Ozone was then passed through
the solution until the reaction was complete. Next, NaBH4
(40 mg, 1.016 mmol) was added to the reaction mixture, which
was then warmed to room temperature. The mixture was washed
with saturated NH4Cl, saturated NaHCO3, and brine, and then dried
over MgSO4 and evaporated. Flash column chromatography on sil-
ica gel (ethyl acetate/hexane = 1:2) gave primary alcohol 12 as a
phy to obtain 6 as a colorless oil; [a]
25 = +5.1 (c 0.1, CHCl3); IR
D
(neat) mmax 3435, 2988, 2955, 2933, 2858, 2702, 1659, 1477,
1402, 1309, 1212, 1179, 1074, 1041, 970, 844, 776, 702,
672 cmꢀ1 1H NMR (CDCl3, 500 MHz) d 0.17 (s, 3H), 0.18 (s, 3H),
;
0.89 (s, 9H), 2.90 (d, J = 2.6 Hz, 1H), 3.79 (s, 3H), 3.84 (dd, J = 5.8,
0.9 Hz, 1H), 4.06 (t, J = 2.0 Hz, 1H), 4.48 (tt, J = 5.8, 1.2 Hz, 1H),
4.85 (d, J = 2.6 Hz, 1H), 5.27 (dt, J = 10.5, 1.3 Hz, 1H), 5.43 (dt,
J = 17.5, 1.5 Hz, 1H), 5.84 (ddd, J = 17.1, 10.6, 6.2 Hz, 1H), 6.88 (m,
2H), 7.11 (m, 2H), 7.41–7.44 (m, 2H), 7.46–7.48 (m, 1H), 8.04–
8.06 (m, 2H); 13C NMR (CDCl3, 125 MHz) d ꢀ4.15, ꢀ3.92, 18.28,
25.94, 31.13, 55.52, 62.63, 70.37, 72.90, 74.77, 114.26, 118.37,
127.67, 128.35, 128.51, 130.88, 133.21, 135.52, 159.12; HRMS
(FAB+): calcd. for C26H36NO4Si [M+H]+ 454.2414, found 454.2414.
colorless oil; [a]
25 = +28.5 (c 0.3, CHCl3); IR (neat) mmax 3312,
D
2955, 2929, 2858, 1655, 1614, 1514, 1465, 1354, 1290, 1253,
1201, 1179, 1119, 1078, 1033, 966, 937, 866, 836, 784, 739,
702 cmꢀ1 1H NMR (CDCl3, 500 MHz) d 0.14 (s, 3H), 0.15 (s, 3H),
;
0.88 (s, 9H), 3.11 (s, 3H), 3.83 (m, 1H), 4.01 (ddd, J = 21.5, 11.0,
6.0 Hz, 1H), 4.09 (m, 1H), 4.28 (td, J = 8.0, 1.5 Hz, 1H), 4.85 (d,
J = 3.0 Hz, 1H), 5.03 (m, 1H), 6.88 (m, 2H), 7.12 (m, 2H), 7.40–
7.49 (m, 3H), 8.02 (m, 2H); 13C NMR (CDCl3, 125 MHz) d ꢀ4.21,
ꢀ3.98, 18.27, 25.89, 31.13, 38.85, 55.53, 61.83, 68.81, 72.04,
82.94, 114.35, 127.70, 128.46, 130.99, 132.66, 155.28, 159.26;
4.8.
(R)-1-((4R,5R,6R)-5-(tert-Butyldimethylsilyloxy)-4-(4-
methoxyphenyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazin-6-yl)prop-
C
26H38NO7SSi [M+H]+ 536.2138; found 536.2137.
2-en-1-ol 60
4.11. (2R,3R,4R,5R)-4-(tert-Butyldimethylsilyloxy)-2-(hydroxy-
methyl)- 5-(4-methoxyphenyl) pyrrolidin-3-ol 5
Crude oil; [a] mmax 3342, 2955,
25 = +30.3 (c 0.4, CHCl3); IR (neat)
D
2929, 2858, 1652, 1614, 1585, 1514, 1465, 1365, 1343, 1283, 1249,
1201, 1179, 1115, 1078, 1033, 952, 929, 884, 866, 836, 806, 780,
A suspension of synthesized mesylate compound 12 (300 mg,
0.56 mmol) in MeOH/AcOH (7.5 mL:0.83 mL) in the presence of
20% Pd(OH)2/C (300 mg) at room temperature was hydrogenated
at atmospheric pressure for 48 h. The catalyst was then removed
by filtration through a Celite pad, and the filtrate was evaporated
to dryness. After washing with EtOAc, the residue was neutralized
with NaHCO3 in water and EtOAc. The organic layer was washed
747, 702, 680 cmꢀ1 1H NMR (CDCl3, 700 MHz) d 0.08 (s, 3H),
;
0.14 (s, 3H), 0.89 (s, 9H), 2.50 (br s, 1H), 3.79 (s, 3H), 3.85 (dd,
J = 7.8, 2.3 Hz, 1H), 4.21 (dd, J = 3.5, 2.0 Hz, 1H), 4.47–4.52 (m,
1H), 4.82 (d, J = 3.5 Hz, 1H), 5.30 (dt, J = 10.6, 1.5 Hz, 1H), 5.42
(dt, J = 17.5, 1.5 Hz, 1H), 5.84 (dt, J = 17.1, 1.6 Hz, 1H), 6.03 (dd,
J = 10.6, 5.5 Hz, 2H), 6.06 (dd, J = 10.5, 5.6 Hz, 1H), 6.85–6.89 (m,
2H), 7.12–7.16(m, 2H), 7.38–7.42 (m, 2H), 7.44–7.48 (m, 1H),
with brine, dried over MgSO4 and evaporated to give 5 as a crude
8.00–8.04 (m, 2H); 13C NMR (CDCl3, 125 MHz)
d
ꢀ15.23,
25
oil (220 mg, 75%). Rf = 0.48 (ethyl acetate/hexane = 1:1); [
a]
=
D
ꢀ0.4336, 18.25, 25.96, 31.13, 55.54, 62.15, 69.40, 71.33, 74.30,
114.20, 117.14, 127.71, 128.29, 128.72, 130.84, 133.46, 133.58,
137.72, 155.13, 159.12, 207.05; HRMS (FAB+): calcd. for
+7.6 (c 0.1, CHCl3); IR (neat) mmax 3346, 2955, 2929, 2858, 1737,
1614, 1588, 1518, 1465, 1447, 1413,1391, 1365, 1253, 1182,
1153, 1041, 944, 840, 784, 732, 713, 676 cmꢀ1 1H NMR (CDCl3,
;
C
26H36NO4Si [M+H]+ 454.2414, found 454.2414.
700 MHz) d ꢀ0.28 (s, 3H), ꢀ0.07 (s, 3H), 0.81 (s, 9H), 3.35 (br s,
1H), 3.65-3.70 (m, 2H), 3.81 (s, 3H), 3.92 (d, J = 7.1 Hz, 1H), 3.98-
4.02 (m, 2H), 6.88 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H); 13C
NMR (CDCl3, 125 MHz) d ꢀ4.97, ꢀ4.63, 17.88, 25.69, 25.74, 55.29,
62.45, 63.54, 66.43, 79.29, 85.64, 114.02, 128.35, 133.60, 159.20;
HRMS (FAB+): calcd. for C18H31NO3Si [M+H]+ 354.2101; found
354.2102.
4.9.
(S)-1-((4R,5R,6S)-5-(tert-Butyldimethylsilyloxy)-4-(4-
methoxyphenyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazin-6-yl)allyl
methanesulfonate
Triethylamine (0.29 mL, 2.058 mmol) and methanesulfonyl
chloride (0.11 mL, 1.372 mmol) were successively added to a solu-
tion of anti,syn,syn-oxazine 6 (0.31 g, 0.686 mmol) in dichloro-
methane (13.7 mL) at 0 °C. The reaction mixture was stirred at
0 °C for 1 h and then warmed to room temperature over 1 h. After
the addition of water, the aqueous layer was extracted with
dichloromethane. The dichloromethane extracts were washed with
saturated NH4Cl, saturated NaHCO3, and brine, and then dried and
evaporated. Flash column chromatography on silica gel (ethyl acet-
ate/hexane = 1:4) gave mesylate (0.36 g, 0.677 mmol) as a colorless
4.12. (2R,3R,4R,5R)-4-(Hydroxy)-2-(hydroxymethyl)-5-(4-hydroxy-
phenyl) pyrrolidin-3-ol 2
Boron tribromide (1.0 M solution in CH2Cl2; 0.427 mL,
0.427 mmol) was added dropwise at 0 °C to a solution of pyrro-
lidine 3 (30.2 mg, 0.0854 mmol) in CH2Cl2 (1.71 mL). The reaction
mixture was stirred for 5 h at room temperature and then
quenched with MeOH. The mixture was diluted with H2O and
washed with EtOAc. The aqueous layer was evaporated, and the
residue was purified by flash column chromatography (silica gel,
oil; [
1659, 1614, 1585, 1514, 1465, 1421, 1361, 1305, 1287, 1253,
1201, 1179, 1115, 1074, 1037, 940, 870, 836, 780, 702, 676 cmꢀ1
a]
25 = +17.7 (c 0.1, CHCl3); IR (neat) mmax 2955, 2933, 2858,
D
;
chloroform/methanol = 1:1) to give 2ꢁHBr.
MeOH); IR(neat) mmax 3353, 2959, 2929, 2854, 1640, 1525, 1462,
1417, 1253, 1019 cmꢀ1 1H NMR (CDCl3, 700 MHz) d 3.52 (br s,
[a]
25 = +41.3(c 0.1,
D
1H NMR (CDCl3, 500 MHz) d 0.14 (s, 3H), 0.19 (s, 3H), 0.89 (s,
9H), 3.04 (s, 3H), 3.80 (s, 3H), 3.95 (m, 1H), 4.00 (d, J = 8.5 Hz,
1H), 4.88 (d, J = 1.5 Hz, 1H), 5.37 (t, J = 8.0 Hz, 1H), 5.48 (m, 1H),
5.62 (m, 1H), 5.64–5.80 (m, 2H), 6.88 (m, 2H), 7.09 (m, 2H),
7.40–7.49 (m, 3H), 8.06 (m, 2H); 13C NMR (CDCl3, 125 MHz) d
ꢀ3.98, ꢀ3.74, 18.35, 25.96, 31.13, 39.49, 55.53, 62.22, 68.52,
82.54, 114.36, 123.39, 127.76, 128.42, 130.41, 130.95, 133.55,
159.21, 207.06.
;
1H), 3.85 (dd, J = 11.3, 5.8 Hz, 1H), 3.90 (dd, J = 12.8, 3.6 Hz, 1H),
4.12 (t, J = 7.7 Hz, 1H), 4.23 (br s, 1H), 4.35 (br s, 1H), 6.99 (d,
J = 8.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H); 13C NMR (CDCl3, 175 MHz)
d 60.13, 61.55, 63.08, 75.33, 79.37, 115.96, 129.62, 156.38. Further
purification with Dowex 50WX8 afforded 2 as a white solid
Please cite this article in press as: Kim, J.-S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.01.009

6
J.-S. Kim et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
(11.3 mg, 0.0683 mmol, 59%); [a]
19 = +42.8 (c 0.04, MeOH); HRMS
D
4. Shibano, M.; Tsukamoto, D.; Masuda, A.; Tanaka, Y.; Kusano, G. Chem. Pharm.
Bull. 2001, 49, 1362–1365.
(FAB+): calcd. for C11H16NO4 [M+H]+ 226.1079, found 226.1073.
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Roberts, P. M.; Thomson, J. E.; West, C. J. Tetrahedron 2012, 68, 4302–4319; (b)
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2227; (e) Chandrasekhar, S.; Saritha, B.; Jagadeshwar, V.; Prakash, S. J.
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Jagadeshwar, V.; Prakash, S. J. Tetrahedron Lett. 2005, 46, 3127–3129; (g)
Haddad, M.; Larcheveque, M. Synlett 2003, 274–276; (h) Toyao, A.; Tamura, O.;
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Acknowledgements
This research was supported by the National Research Founda-
tion of Korea (NRF) through the Basic Science Research Program.
Further support by the South Korean Ministry of Education, Science
and Technology (2010-0022900) and Yonsung Fine Chemicals
Corporation is appreciated. The Global Ph.D. Fellowship Grants to
S.H.P. are gratefully acknowledged.
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Please cite this article in press as: Kim, J.-S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.01.009