A concise synthesis of (-)-lentiginosine via an anti,syn-oxazine

Article abstract of DOI:10.1016/j.tetasy.2013.11.009

A concise and stereocontrolled total synthesis of (-)-lentiginosine, a potent glycosidase inhibitor, has been achieved. Starting from anti,syn-oxazine as a chiral building block, the key features in these strategies are the Wittig reaction and cyclization

Full text of DOI:10.1016/j.tetasy.2013.11.009

Tetrahedron: Asymmetry 25 (2014) 87–91
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A concise synthesis of (ꢀ)-lentiginosine via an anti,syn-oxazine
Gun-Woo Kim, Tian Jin, Jin-Seok Kim, Seok-Hwi Park, Kun-Hee Lee, Seong-Soo Kim,
⇑
In-Soo Myeong, Won-Hun Ham
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and stereocontrolled total synthesis of (ꢀ)-lentiginosine, a potent glycosidase inhibitor, has
been achieved. Starting from anti,syn-oxazine as a chiral building block, the key features in these strate-
gies are the Wittig reaction and cyclization.
Received 29 September 2013
Accepted 7 November 2013
Available online 14 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
In a previous report, we found that the palladium(0)-catalyzed
oxazine formation of c-allyl benzamide, with a benzoyl substituent
Polyhydroxylated indolizidine alkaloids such as swainsonine,
castanospermine, and lentiginosine are known to be potential gly-
cosidase inhibitors.1,2 Among them, the least hydroxylated lentigi-
nosine was isolated from the leaves of Astragalus lentiginous in
1990;3 (ꢀ)-lentiginosine 1 was found to be a selective inhibitor
(IC50 5 mg/mL) of amyloglucosidase, an enzyme that hydrolyzes
as an N-protecting group in the presence of Pd(PPh3)4, NaH, and
n-Bu4NI might proceed with high stereoselectivity. The bulk of
the protecting group on the secondary alcohol is responsible for
controlling the diastereoselectivity of oxazine ring formation6
(Scheme 1). This process efficiently adjusted the stereochemistry
1,4- and 1,6-a-glucosidic linkages, and also exhibits anti-HIV activ-
ity.4 Several synthetic approaches to this structure have been
reported5 (Fig. 1). In recent representative publications, Liu et al.
OTBS
OTBS
R
Pd(PPh3)4, NaH
R
Cl
N
O
n-Bu4NI, THF
0oC : 57-65%
12-30:1
NHBz
Ph
OH
H
R = (a) C6H5, (b) C6H5CH2, (c) (CH3)2CH, (d) (CH3)2CHCH2, (e) TBSOCH2
OH
N
Scheme 1. Oxazine formation catalyzed by Pd(0).
(-)-lentiginosine
and provided simultaneous protection for the newly generated hy-
droxyl group. The synthetic utility of anti,syn-oxazines as chiral
building blocks has been demonstrated by their successful
application to the synthesis of biologically active natural products
Figure 1. Structure of (ꢀ)-lentiginosine.
such as DAB-1,
D
-fagomine,
D-lyxo-phytosphingosine, and
pachastrissamine.7a,b
demonstrated an asymmetric synthesis of (ꢀ)-lentiginosine by a
double aza-Michael reaction.5a Kim et al. reported a facile synthe-
sis of lentiginosine analogues based on a highly regio- and diaste-
reoselective allylic amination using chlorosulfonyl isocyanate.5b
Azzouz et al. also described a concise synthesis of lentiginosine
derivatives using pyridinium formation via a Mitsunobu reaction.5e
These routes give products with good enantiopurity but are limited
in terms of access to structural analogues.
As part of the expansion of the synthetic utility of chiral
anti,syn-oxazines, we have also been exploring the development
of a novel strategy for the concise total synthesis of a bicyclic nat-
ural product. Herein we report a straightforward procedure for the
highly stereocontrolled total synthesis of (ꢀ)-lentiginosine 1. We
envisioned that our intramolecular palladium(0)-catalyzed oxazine
formation reaction could be utilized to set the three contiguous
stereocenters of (ꢀ)-lentiginosine 1.
As shown in Scheme 2, our retrosynthetic analysis suggested
that (ꢀ)-lentiginosine 1 could be easily obtained from a common
⇑
Corresponding author. Tel.: +82 31 290 7706; fax: +82 31 292 8800.
E-mail address: whham@skku.edu (W.-H. Ham).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.11.009

88
G.-W. Kim et al. / Tetrahedron: Asymmetry 25 (2014) 87–91
OH
HO
OTBS
H
HO
OTBS
OH
N
OBn
N
OMs
N
Boc
Boc
3
1
2
(-)-lentiginosine
OTBS
BzO
OTBS
OTBS
TBSO
N
O
N
H
Ph
5
4
Scheme 2. Retrosynthesis of (ꢀ)-lentiginosine 1.
intermediate, anti,syn-oxazine 5. (ꢀ)-Lentigonosine 1 could be pre-
pared from compound 2 by cyclization. Compound 2 could be syn-
thesized by hydrogenation of 3 and subsequent mesylation of the
primary hydroxyl group. Compound 3 could be converted from
compound 4 by Wittig reaction and DMP oxidation. The vinyl
group of anti,syn-oxazine 5 could be converted into the corre-
sponding aldehyde, which could be employed in the formation of
the pyrrolidine ring via catalytic hydrogenation of anti,syn-oxazine
by cleavage of the carbamate moiety followed by cyclization of the
intermediate aminoaldehyde with 78% yield (two steps), as shown
in Scheme 3.
As shown in Scheme 4, the pyrrolidine ring 4 was protected
with Boc2O. The N-Boc compound 4 was reacted with HF–pyridine
to afford the selectively deprotected free primary alcohol in good
yield. Oxidation of the primary hydroxyl group 7 with Dess–Martin
periodinane produced the corresponding aldehyde, which was
subsequently reacted with (3-benzyloxypropyl)triphenylphospho-
nium bromide in the presence of 3.0 equiv of n-BuLi in THF at 0 °C
to give the debenzoylated olefin 3 in moderate yield.8 Catalytic
hydrogenation of 3 with Pd/C produced 2 by simultaneous depro-
tection of the benzyl group and reduction of the internal olefin.
Mesylation of the primary alcohol gave the mesylate compound
in excellent yield. After removal of the Boc and TBS groups with
4 M HCl–dioxane solution, subsequent cyclization (effected by
treatment of NaOH) afforded (ꢀ)-lentiginosine 1 in 65% yield
5. Therefore, anti,syn-oxazine 5 was prepared from N-benzoyled-D-
serine methyl ester according to a known procedure by palla-
dium(0) catalyzed oxazine formation reaction.7b,10
2. Results and discussion
Under the reported conditions,7b anti,syn-oxazine 5 was treated
with benzyl chloroformate in the presence of aqueous NaHCO3
(Schotten–Baumann conditions), to afford the carbamate product
6 in 85% yield. Ozonolysis of the terminal olefin gave the corre-
sponding aldehyde. Hydrogenolysis of the aldehyde in MeOH was
performed under 70 psi of H2 catalyzed by Pd(OH)2 at ambient
temperature. Under these conditions, a single isomer 4 was formed
(two steps).9 The specific rotation of 1, ½a 2D5
¼ ꢀ3:2 (c 1.0, MeOH),
ꢁ
compared to the reported values, ½a D25
ꢁ
¼ ꢀ3:0 (c 0.3, MeOH),5a
½
a 2D5
ꢁ
¼ ꢀ3:05 (c 1.0, MeOH),5g confirmed the absolute configura-
tion of 1.
OTBS
OTBS
BzO
OTBS
OTBS
1. O3, MeOH
1. CbzCl, NaHCO3
TBSO
TBSO
CbzHN
2. Pd(OH)2/C, H2
78% (2 steps)
N
O
CH2Cl2, H2O
85%
N
H
OBz
Ph
4
5
6
Scheme 3. Synthesis of the pyrrolidine ring.
HO
BzO
OTBS
OTBS
OH
1. DMP, CH2Cl2
1. TEA, Boc2O
4
2. n-BuLi, THF, -78OC
2. HF-pyridine
81% (2steps)
OBn
N
N
Boc
Boc
3
7
BrPh3P
61%(2 steps)
OBn
OH
H
N
HO
OTBS
1. MsCl, TEA
H2, Pd/C
OH
2. 4M HCl-dioxane solution
1M NaOH
MeOH
75%
OH
N
65% (2 steps)
Boc
1
2
(-)-lentiginosine
Scheme 4. Synthesis of (ꢀ)-lentiginosine 1.

G.-W. Kim et al. / Tetrahedron: Asymmetry 25 (2014) 87–91
89
The spectroscopic (1H and 13C NMR) data for synthetic 1 were
fully identical with those of synthetic compounds and the proper-
ties of 1 showed good agreement with those reported.5a,g,f
(1.24 g, 85%) as a colorless oil; Rf = 0.67 (ethyl acetate/hexane =
1/6); ½a 2D5
ꢁ
¼ þ39:6 (c 1.0, CHCl3); IR (neat)
mmax: 3455, 2952,
2857, 1724, 1260, 1103, 930 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d
0.03–0.10 (m, 12H), 0.86 (s, 9H), 0.88 (s, 9H), 3.75 (dd, J = 4.7,
10.0 Hz, 2H), 3.92 (dd, J = 5.4, 10.0 Hz, 1H), 4.16 (t, J = 5.1 Hz, 1H),
5.04–5.14 (m, 2H), 5.29–5.43 (m, 2H), 5.64 (t, J = 5.6 Hz, 1H), 6.04
(ddd, J = 6.2, 10.7, 17.2 Hz, 1H), 7.32–7.41 (m, 7H), 7.52–7.57 (m,
1H), 8.05 (d, J = 7.3 Hz, 1H); 13C NMR (CDCl3, 125 MHz) d ꢀ5.26,
ꢀ5.16, ꢀ4.46, ꢀ4.13, 0.21, 18.39, 26.09, 54.92, 61.42, 66.81,
72.67, 76.57, 118.82, 128.17, 128.21, 128.67, 129.89, 130.47,
133.89, 133.27, 136.94, 156.64, 165.61; HRMS (FAB+) (M++H) m/z
calcd for C33H51NO6Si2 614.3333 found 614.3331.
3. Conclusion
In conclusion, we have shown that the indolizidine alkaloid
(ꢀ)-lentiginosine can be readily obtained through a convergent se-
quence starting from a chiral 1,3-oxazine. The key features in these
strategies are the Wittig reaction and cyclization. The net results
were the synthesis via a linear sequence of 10 steps from
anti,syn-oxazine 5 in 15.7% overall yield for (ꢀ)-lentiginosine 1.5
4.2.3. (3R,4R,5R)-4-(tert-Butyldimethylsilyloxy)-5-((tert-butyldi-
methylsilyloxy)methyl)pyrrolidin-3-yl-benzo-ate 4
4. Experimental section
4.1. General
Alkene 6 (1.24 g, 2.02 mmol) was dissolved in dry methanol
(50 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 (1.5 mL) and allowed to warm to room
temperature. The solvents were evaporated under reduced pressure.
The crude aldehyde was immediately employed in the next step
without further purification. A solution of the aldehyde in MeOH
(30 mL), to which was added 620 mg of 20% Pd(OH)2/C, was vigor-
ously shaken under 75 psi H2 for 24 h at ambient temperature. The
mixture was then filtered through a pad of silica and concentrated
in vacuo. Purification by column chromatography over silica gel
(ethyl acetate/hexane = 1/10) gave the pyrrolidine 4 (734 mg, 78%
for two steps) as a colorless oil; Rf = 0.38 (ethyl acetate/hex-
Optical rotations were measured on a polarimeter in the solvent
specified. 1H NMR and 13C NMR spectra were obtained from Coop-
erative Center for Research Facilities in Sungkyunkwan University
on FT-NMR 125, 175, 500, or 700 MHz spectrometers. Chemical
shift values are reported in parts per million relative to TMS or
CDCl3 as an internal standard and coupling constants in Hertz. IR
spectra were measured on a FT-IR spectrometer. Mass spectro-
scopic data were obtained from the Korea Basic Science Institute
(Daegu) on Jeol JMS 700 high resolution mass spectrometer. Flash
chromatography was executed using mixtures of ethyl acetate and
hexane as eluents. Unless otherwise noted, all non-aqueous reac-
tions were carried out under an argon atmosphere with commer-
cial grade reagents and solvents. Tetrahydrofuran (THF) was
distilled over sodium and benzophenone (indicator). Methylene
chloride (CH2Cl2) was distilled from calcium hydride.
anes = 1/2); ½a 2D5
ꢁ
¼ ꢀ39:2 (c 1.0, CHCl3); IR (neat)
mmax: 2941,
2859, 1722, 1462, 1388, 1263, 1107, 841 cmꢀ1
;
1H NMR (CDCl3,
300 MHz) d 0.04–0.14 (m, 12H), 0.93–0.96 (m, 18H), 2.14 (s, br,
1H, NH), 3.02–3.14 (m, 2H), 3.45 (dd, J = 5.7, 13.2 Hz, 1H), 3.78 (dd,
J = 4.5, 10.0 Hz, 1H), 3.86 (dd, J = 4.5, 10.2 Hz, 1H), 4.34–4.37 (m,
1H), 5.19–5.23 (m, 1H), 7.30–7.49 (m, 2H), 7.57–7.63 (m, 1H),
8.05–8.08 (m, 2H); 13C NMR (CDCl3, 125 MHz) d ꢀ5.27, ꢀ5.22,
ꢀ4.73, ꢀ4.33, 18.17, 18.53, 25.97, 26.12, 51.92, 62.14, 68.13, 78.21,
83.67, 128.58, 129.86, 130.32, 133.26, 166.27; HRMS (FAB+)
(M++H) m/z calcd for C24H44NO4Si2 466.2809 found 466.2802.
4.2. Experimental procedures
4.2.1. (4R,5R,6R)-5-(tert-Butyldimethylsilyloxy)-4-((tert-butyl-
dimethylsilyloxy)methyl)-2-phenyl-6-vinyl-5,6-di-hydro-4H-
1,3-oxazine 5
Colorless oil; Rf = 0.5 (ethyl acetate/hexane = 1/30); ½a D25
¼ þ3:8
ꢁ
4.2.4. (2R,3R,4R)-tert-Butyl 4-(benzoyloxy)-3-(tert-butyl-dimeth-
ylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carb-oxylate 7
(c 1.0, CHCl3); IR (neat) mmax: 2929, 2360, 1661, 1471, 1254, 1115,
836, 777 cmꢀ1 1H NMR (300 MHz, CDCl3) d 0.08–0.20 (m, 12H),
;
To a solution of 4 (734 mg, 1.58 mmol) in methanol (15.8 mL)
was added triethylamine (0.26 mL, 1.89 mmol) via syringe fol-
lowed by di(tert-butyl)dicarbonate (413 mg, 1.89 mmol) in one
portion. The reaction mixture was then stirred for 4 h after which
the resulting yellow solution was poured into NH4Cl. The layer was
separated, and the organic layer was washed with water. The or-
ganic layer was dried over MgSO4, filtered, and the solvent was re-
moved in vacuo. The crude compound was purified by flash
column chromatography (ethyl acetate/hexane = 1/15) to afford
Boc protected pyrrolidine 7 (855 mg, 96%) as a colorless oil;
0.88–0.96 (m, 18H), 3.47 (dd, J = 3.0, 5.0, 8.0 Hz, 1H), 3.83 (dd,
J = 5.0, 10.0 Hz, 1H), 4.02 (dd, J = 3.0, 10.0 1H), 4.21 (dd, J = 4.0,
7.0 Hz, 1H), 4.80 (ddd, J = 2.0, 4.0, 7.0 Hz, 1H), 5.35 (ddd, J = 1.0,
2.0, 7.0 Hz, 1H), 5.40 (ddd, J = 1.0, 2.0, 13.0 Hz, 1H), 6.10 (ddd,
J = 5.0, 10.5, 17.0 Hz, 1H), 7.38–7.47 (m, 3H), 8.01–8.04 (m, 2H);
13C NMR (125 MHz, CDCl3) d ꢀ5.04, ꢀ4.99, ꢀ4.51, ꢀ4.35, 18.27,
18.55, 26.00, 26.13, 26.27, 59.62, 64.13, 65.35, 75.93, 117.54,
127.62, 128.21, 130.59, 133.72, 133.79, 154.43; HRMS (FAB+)
(M++H) m/z calcd for C25H44NO3Si2 462.2860 found 462.2860.
Rf = 0.73 (ethyl acetate/hexane = 1/6); ½a D25
¼ ꢀ10:1 (c 1.0, CHCl3);
ꢁ
4.2.2. (3R,4R,5R)-5-(Benzyloxycarbonylamino)-4,6-bis (tert-butyl-
dimethylsilyloxy)hex-1-en-3-yl benzoate 6
IR (neat) mmax: 2995, 2931, 2886, 2858, 1727, 1703, 1106, 1073,
837, 778 cmꢀ1 1H NMR (CDCl3, 500 MHz) d 0.03–0.15 (m, 12H),
;
To a solution of oxazine 5 (1.1 g, 2.38 mmol) in CH2Cl2 (15.9 mL)
was added a solution of NaHCO3 (800 mg, 9.53 mmol) in water
(15.9 mL), and the mixture was cooled in an ice bath. To this solu-
tion was added dropwise a solution of benzyl chloroformate
(0.68 mL, 4.76 mmol). The mixture was stirred at room tempera-
ture for 24 h. Next, benzyl chloroformate (0.68 mL, 4.76 mmol)
was added. The mixture was continued stirring (24 h) until TLC
indicated that the reaction was complete. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2
(2 ꢂ 20 mL). The combined organic layer was washed with water,
dried (MgSO4), and concentrated in vacuo. Purification by silica
gel chromatography (ethyl acetate/hexane = 1/15) gave alkene 6
0.83 (s, 9H), 0.89 (s, 9H), 1.47 (d, J = 11 Hz, 9H), 3.40–3.96 (m,
5H), 4.53 (d, J = 16.5 Hz, 1H), 5.17 (d, J = 12.5 Hz, 1H), 7.44 (t,
J = 7.0 Hz, 2H), 7.57 (t, J = 7.0 Hz, 1H), 8.01 (t, J = 8.5 Hz, 2H); 13C
NMR (CDCl3, 175 MHz) d ꢀ5.42, ꢀ5.18, ꢀ4.64, ꢀ4.48, 18.11,
25.92, 26.02, 28.70, 50.91, 61.44, 67.23, 75.53, 78.94, 128.67,
129.87, 130.00, 133.45, 154.91, 165.58; HRMS (FAB+) (M++H) m/z
calcd for C29H51NO6Si2 566.3333 found 566.3330.
To
a
solution of Boc protected pyrrolidine (855 mg,
1.511 mmol) in THF (15 mL) were added pyridine (5.04 mL) and
a buffered HF–pyridine solution (1.51 mL, 1.511 mmol) at 0 °C.
The reaction mixture was then stirred at room temperature for
4 h before being quenched with saturated aqueous NaHCO3. The

90
G.-W. Kim et al. / Tetrahedron: Asymmetry 25 (2014) 87–91
mixture was extracted with EtOAc (50 mL ꢂ 3) and the organic
layer was washed with distilled water and saturated CuSO4 solu-
tion, brine, dried with Na2SO4, and concentrated in vacuo. Purifica-
tion by flash chromatography (ethyl acetate/hexane = 1/6) afforded
primary alcohol 7 (564 mg, 83%) as crude oil; Rf = 0.53 (ethyl ace-
175 MHz) d ꢀ4.68, ꢀ4.56, 15.07, 17.91, 22.68, 26.43, 28.51, 29.70,
62.99, 66.74, 75.52, 76.18, 80.07, 80.67, 155.21; HRMS (FAB+)
(M++H) m/z calcd for C19H39NO5Si 390.2676 found 390.2678.
4.2.7. (1R,2R,8aR)-Octahydroindolizine-1,2-diol 1 [(ꢀ)-lentig-
inosine]
tate/hexane = 1/2); ½a D25
ꢁ
¼ ꢀ15:3 (c 1.0, CHCl3); IR (neat) mmax
:
3435, 2954, 2931, 2887, 2858, 1725, 1701, 1407, 1368, 1268,
To a solution of 2 (220 mg, 0.567 mmol) in CH2Cl2 (1.13 mL) at
0 °C were successively added triethylamine (0.08 mL), and MsCl
(0.05 mL). The reaction mixture was then stirred at 0 °C for 2 h,
after which water was added. The aqueous layer was extracted
with CH2Cl2. The organic layer was washed with saturated NH4Cl,
NaHCO3, and brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by short flash chromatography on a silica
gel column (chloroform/methanol = 10/1) to afford a mesylate
compound. To the mesylate compound (198 mg, 0.423 mmol)
was added a 4 M HCl–dioxane solution (1.1 mL). The mixture
was stirred for 12 h. The mixture was evaporated to dryness and
the residue was taken up in water (1.1 mL) and washed three times
with CH2Cl2 (1.1 mL). The organic layer was back-extracted with
water (1.1 mL), and the combined aqueous fractions were adjusted
to pH 13 with 1 M NaOH, allowed to stir for 1 h, and extracted with
CH2Cl2. The combined organic extracts were dried over MgSO4, and
concentrated in vacuo to give lentiginosine 1 (56 mg, 65% for two
steps) as a white solid; Rf = 0.32 (chloroform/methanol = 6/1); Mp
1109, 838, 779, 712 cmꢀ1 1H NMR (CDCl3, 500 MHz) d 0.15 (m,
;
6H), 0.89 (s, 9H), 1.49 (s, 9H), 3.53 (dd, J = 1.0, 12.5 Hz, 1H), 3.80–
3.90 (m, 4H), 4.15 (s, 1H), 4.40 (s, 1H), 5.15 (br, 1H, OH), 7.46 (t,
J = 8.0 Hz, 2H), 7.59 (m, 1H), 8.01 (d, J = 8.5 Hz, 2H); 13C NMR
(CDCl3, 175 MHz) d ꢀ4.67, ꢀ4.44, 18.13, 25.87, 28.61, 51.11,
65.24, 68.65, 77.79, 81.15, 128.77, 129.63, 129.91, 133.66, 154.79,
165.77; HRMS (FAB+) (M++H) m/z calcd for C23H38NO6Si 452.2468
found 452.2466.
4.2.5. (2S,3R,4R)-tert-Butyl 2-((E)-4-(benzyloxy)but-1-enyl)-3-
(tert-butyldimethylsilyloxy)-4-hydroxypyrrolid-ine-1-carbox-
ylate 3
To a solution of Dess–Martin periodinane (2.52 g, 6.25 mmol) in
anhydrous CH2Cl2 (3 mL) was added a solution of primary alcohol 7
(564 mg, 1.25 mmol) in CH2Cl2 (1 mL) at room temperature. The
reaction mixture was then stirred at ambient temperature for
2 h. The mixture was diluted with Et2O after which saturated aque-
ous NaHCO3 (5 mL) and Na2S2O3 (2.39 g) were added and the het-
erogeneous mixture was stirred at room temperature until the
organic layer was clear. The ether layer was washed with brine,
dried over MgSO4, and concentrated in vacuo to give the crude
aldehyde. Next, n-BuLi (2.5 M in hexane, 1.51 mL, 3.76 mmol)
was added dropwise to a mixture of (3-benzyloxypropyl)-triphen-
ylphosphonium bromide (1.85 g, 3.76 mmol) in THF (4 mL) at 0 °C.
After 30 min of stirring at 0 °C, the crude aldehyde (564 mg,
1.25 mmol) dissolved in anhydrous THF (2.3 mL) was added drop-
wise. After 6 h, the reaction was partitioned between Et2O and
H2O. The organic layer was washed with brine, dried over MgSO4,
and concentrated. The residue was purified by chromatography on
102–105 °C; ½a 2D5
ꢁ
¼ ꢀ3:2 (c 1.0, MeOH); IR (neat)
mmax: 3758,
3694, 2987, 1445, 1210, 1130 cmꢀ1
;
1H NMR (D2O, 500 MHz) d
1.05–1.11 (m, 2H), 1.24–1.31 (m, 1H), 1.46 (d, J = 13.5 Hz, 1H),
1.63 (dd, J = 1.5, 10.0 Hz, 1H), 1.75–1.80 (m, 2H), 1.86–1.91 (m,
1H), 2.46 (dd, J = 7.5, 11.5, 1H), 2.66 (dd, J = 2.0, 11.5 Hz, 1H),
2.77 (d, J = 11.5 Hz, 1H), 3.47 (dd, J = 4.0, 9.0 Hz, 1H), 3.91 (m,
1H); 13C NMR (CDCl3, 175 MHz) d 23.02, 23.95, 27.54, 52.64,
50.21, 68.57, 75.65, 82.89; HRMS (FAB+) (M++H) m/z calcd for
C8H16NO2 158.1181 found 158.1184.
Acknowledgments
a
silica gel column (ethyl acetate/hexane = 1/6) to afford
3
This research was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF),
which is funded by the Ministry of Education, Science and Technol-
ogy (NRF-2010-0022900; NRF-2011-0029199) and by Yonsung
Fine Chemicals Corporation. The Global Ph.D. Fellowship Grant to
S.H.P. is gratefully acknowledged.
(358 mg, 61% for two steps) as a colorless oil; Rf = 0.37 (ethyl ace-
tate/hexane = 1/4); ½a D25
ꢁ
¼ ꢀ18:8 (c 1.0, CHCl3); IR (neat) mmax
:
3423, 3064, 3030, 2886, 2857, 1695, 1672, 1473, 1412, 1365,
1307, 1170, 1094, 1000, 838, 778, 737, 698, 671, 609 cmꢀ1 1H
;
NMR (CDCl3, 500 MHz) d 0.07 (m, 6H), 0.87 (m, 9H), 1.49 (s, 9H),
1.62 (s, 2H), 2.36 (dd, J = 4.0, 6.5 Hz, 4H), 2.47 (dd, J = 7.5,
13.5 Hz, 1H), 3.35–3.53 (m, 3H), 3.74–4.04 (m, 2H), 4.31 (s, 1H),
4.49 (d, J = 1.5 Hz, 1H), 4.52 (s, 1H), 5.50–5.60 (m, 2H), 7.27–7.36
(m, 5H); 13C NMR (CDCl3, 175 MHz) d ꢀ4.46, ꢀ4.47, 18.13, 25.90,
28.59, 28.66, 32.85, 52.90, 63.32, 69.68, 69.99, 73.17, 79.64,
82.72, 126.07, 127.86, 128.55, 128.70, 128.75, 130.83, 132.29,
138.70, 155.10; HRMS (FAB+) (M++H) m/z calcd for C26H43NO5Si
478.2989 found 478.2985.
References
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4.2.6. (2S,3R,4R)-tert-Butyl 3-(tert-butyldimethylsilylox-y)-4-
hydroxy-2-(4-hydroxybutyl)pyrrolidine-1-carboxy-late 2
A
suspension of the above olefin compound (358 mg,
0.75 mmol) in MeOH (8 mL) in the presence of 20% Pd(OH)2/C
(210 mg) at room temperature was hydrogenated at atmospheric
pressure overnight. The catalyst was removed by filtration through
a Celite pad. The filtrate was evaporated to dryness. The residue was
purified by a flash column chromatography (silica gel, chloroform/
methanol = 9/1) to give compound 2 (220 mg, 75%) as a colorless
oil; Rf = 0.23 (chloroform/methanol = 10/1); ½a D25
¼ ꢀ18:0 (c 1.0,
ꢁ
MeOH); IR (neat) mmax: 3424, 2954, 2930, 1723, 1469, 1407, 1361,
1270, 1070, 837, 778, 712, 371 cmꢀ1 1H NMR (CDCl3, 500 MHz) d
;
0.09 (d, J = 2.3 Hz, 6H), 0.87 (d J = 2.1 Hz, 9H), 0.98 (m, 1H), 1.25–
1.35(m, 5H) 1.46 (s, 9H), 1.62–1.68 (m, 1H), 3.25–3.68 (m, 5H),
3.98 (m, 2H), 4.07 (s, 1H, OH), 4.14 (s, 1H, OH); 13C NMR (CDCl3,

G.-W. Kim et al. / Tetrahedron: Asymmetry 25 (2014) 87–91
91
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10. The requisite anti,syn-oxazine precursor was prepared in high yield from the
commercially available N-benzoyl-D-serine by the five steps sequence shown
in following scheme.
O
O
LiAlH(OtBu)3
Cl
1. MeNHOMe-HCl, Me3Al
TBSO
EtOH, -78oC
87%
anti:syn = 10:1
TBSO
OCH3
NHBz
n-Bu3Sn
Cl
2. MeLi,
BzHN
81% (2 steps)
OTBS
OH
Pd(PPh3)4, NaH
TBSCl, imidazole
Cl
Cl
TBSO
TBSO
n-Bu4NI, THF, 0oC
DMF
95%
NHBz
81%
NHBz
OTBS
OTBS
TBSO
TBSO
(anti,syn:anti,anti) = 30:1
N
O
N
O
Ph
Ph
anti,anti-oxazine
anti,syn-oxazine