Asymmetric synthesis of (+)-lentiginosine using a chiral aziridine based approach

Article abstract of DOI:10.1016/j.tetasy.2014.02.009

The synthesis of the indolizidine alkaloid, (+)-lentiginosine, is described. A key feature of the preparative route is the efficient and stereoselective construction of a dihydroxylated pyrrolidine via Sharpless asymmetric dihydroxylation of an aziridine-

Full text of DOI:10.1016/j.tetasy.2014.02.009

Tetrahedron: Asymmetry 25 (2014) 497–502
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of (+)-lentiginosine using a chiral aziridine
based approach
Hojong Yoon a, Kyung Seon Cho a, Taebo Sim a,b,
⇑
a Chemical Kinomics Research Center, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul 136-791, Republic of Korea
b KU-KIST Graduate School of Converging Science and Technology, 145, Anam-ro, Seongbuk-gu, Seoul 136-713, 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 synthesis of the indolizidine alkaloid, (+)-lentiginosine, is described. A key feature of the preparative
route is the efficient and stereoselective construction of a dihydroxylated pyrrolidine via Sharpless asym-
metric dihydroxylation of an aziridine-enoate, which was prepared from commercially available 1-(S)-a-
methylbenzylaziridine-2-methanol. In addition, a regioselective aziridine-to-pyrrolidinone ring expan-
sion process followed by a Wittig olefination was employed to construct a late stage pyrrolidine interme-
diate that was transformed into (+)-lentiginosine.
Received 7 November 2013
Accepted 11 February 2014
Available online 14 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
treatment of type II diabetes mellitus,4 and miglistat (N-butyl-
deoxynojirimycin, ZavescaÒ), a drug employed for the treatment
Glycosidases are enzymes that catalyze glycoside hydrolysis
reactions that occur in numerous anabolic/catabolic processes in
living systems.1 Since blocking these enzymes can be used as a
general strategy to treat various diseases, the development of po-
tent and selective glycosidase inhibitors is in high demand. Since
nojirimycin, a natural glycosidase inhibitor, was isolated and char-
acterized from a Streptomyces strain in 1966,2 a number of glycosi-
dase inhibitors that possess carbosugar and iminosugar like
structures have been developed. These inhibitors have received
great attention because of their interesting anti-diabetic, anti-
tumor metastasis, anti-HIV, anti-influenza, and pharmaceutical
properties.3 Especially interesting in this regard are the iminosugar
type glycosidase inhibitors miglitol (GlysetÒ), a drug used for the
of Gaucher’s disease.5
(+)-Lentiginosine 1, an indolizidine alkaloid that was first iso-
lated from Astragalus lentiginosus in 1990 by Elbein et al.6 (Fig. 1),
has been reported to be a selective and highly potent inhibitor
(IC50 = 0.43 l
g/L) on amyloglucosidase.1 Furthermore, Piaz et al.
in 2011 reported that (+)-lentiginosine has anti-Hsp90 activity.7
These observations make this dihydroxylated indolizidine an inter-
esting lead compound for drug discovery. In addition to its inter-
esting biological activities, (+)-lentiginosine 1 has an attractive
chemical structure because it contains three contiguous and func-
tionalized stereogenic centers. As a consequence of these features,
new strategies for the preparation of this iminosugar would have
both synthetic and biomedical significance.
OH
H
N
HO
HO
OH
OH
OH
H
N
H
N
H
N
HO
HO
OH
OH
OH
OH
(+)-lentiginosine 1
(+)-swainsonine
(-)-steviamine
(+)-castanospermine
Figure 1. Naturally occurring polyhydroxylated indolizidines.
⇑
Corresponding author. Tel.: +82 2 958 6437; fax: +82 2 958 5189.
E-mail address: tbsim@kist.re.kr (T. Sim).
http://dx.doi.org/10.1016/j.tetasy.2014.02.009
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

498
H. Yoon et al. / Tetrahedron: Asymmetry 25 (2014) 497–502
Several routes have been developed for the synthesis of (+)-len-
developed various conditions for carrying out dihydroxylation
reactions for aziridine-enoate type substrates in an earlier effort,19
a brief exploratory study was conducted to uncover an ideal meth-
od for the conversion of (E)-3-(aziridin-2-yl)acrylate 5 into diol 4.
Dihydroxylation of 5 employing conditions described by Dono-
hoe et al. (OsO4/TMEDA complex)20 did not yield the desired prod-
uct. In addition, catalytic dihydroxylation using OsO4/NMO in the
absence of a chiral ligand resulted in formation of a mixture of
diols 4a and 4b with a low level (3:2) of diastereoselectivity. Both
of these outcomes are consistent with previously reported obser-
vations.21 Sharpless asymmetric dihydroxylation of 5 using AD-
mix-a generated the desired diol 4a with high diastereoselectivity
(4a/4b = 11:1), and which was isolated in 63% yield using silica gel
column chromatography (Table 1).
The C-3 bond of the aziridine ring in diol 4a was cleaved regio-
selectively by using excess AcOH in CH2Cl2 (Scheme 3).22 This pro-
cess furnished a ring opened amine product that subsequently
underwent efficient (72%) lactam forming cyclization23 in toluene
at 90 °C to produce pyrrolidinone 8. It is important to note that this
ring expansion strategy should be applicable to the synthesis of
various polyhydroxylated pyrrolidine alkaloids.24
tiginosine, all of which employ modern synthetic methods to
accomplish the key steps. Successful approaches to this target have
relied on a variety of processes including (1) RCM to generate a
piperidine backbone;8 (2) dihydroxylation of an (E)-unsaturated
ester;8b,9 (3) an Aza-cope rearrangement8b and tandem Mitsunobu
reaction/[3.3]-sigmatropic rearrangement of an azide;10 (4) a
sequential enantioselective diethylzinc addition and [3.3]-sigma-
tropic rearrangement of an allylcyanate;11 (5) intramolecular
radical cyclization of an acylsilane;12 (6) a coupled catalytic asym-
metric Heck-type cyclization and stereoselective epoxidation;13 (7)
stereospecific alkene bromohydration using a chiral b-hydroxy-
c
a
,d-unsaturated sulfoxides;14 (8) asymmetric deoxygenation of
quaternary -hydroxypyrrolidine derivative derived from
a
D
-xylose;15 (9) thermal rearrangement of an isoxazolidine derived
by using a 1,3-dipolar cycloaddition reaction of a nitrone;16 and
(10) organometallic addition to a nitrone followed by reduction
and RCM.17 Importantly, most of reported routes begin with non-
racemic chiral starting materials that are derived from naturally
occurring sugars or acids.8a,c,11–13,16–18
In continuing studies focused on the synthesis of biologically
and structurally interesting alkaloids, we have developed a novel
and efficient approach to the synthesis of (+)-lentiginosine 1,
Protection of the alcohol groups in 8 using TBSOTf afforded the
bis-TBS-ether 9 (91%). Since the simultaneous reduction of both
the acetate and amide groups in 9 using BH3SMe2 resulted in a
low yield of 3 (62%), an alternate route was employed. Accordingly,
hydrolysis of the acetate group with KOH followed by in situ
reduction of the amide group using BH3SMe2 furnished the corre-
sponding hydroxypyrrolidine 3 in high yield (81% over two steps).
Following the strategy proposed for the synthesis of (+)-lentigino-
sine that is outlined retrosynthetically in Scheme 1, the primary
alcohol group in 3 was oxidized using Swern conditions to yield
the corresponding aldehyde, which in a crude form was subjected
to a Wittig 3-carbon homologation process using the benzyloxy-
propylphosphonium salt 12. This reaction produced cis-olefin 2
as a single isomer in high yield (66% over two steps, 2 g scale).
Cleavage of the N-phenylethyl group and reduction of the olefin
moiety in 2 were readily accomplished by utilizing catalytic hydro-
genation with Pd(OH)2 in methanol at room temperature contain-
ing a catalytic amount of TFA. This process produced amino
alcohol 10 in 88% yield as a mixture of a free base and a TFA salt.
Neutralization with triethylamine then gave the free base form of
10. After purification by using silica gel column chromatography,
compound 10 was treated sequentially with CBr4/PPh3 and triethyl-
amine to promote piperidine ring formation, a process that gener-
ated indolizidine 1125 in 74% yield. Finally, removal of the TBS
protecting groups under acidic conditions (3 M HCl) furnished
(+)-lentiginosine 1 in 86% yield. The identity of synthetic (+)-lentig-
inosine 1 was confirmed by showing that its spectroscopic and opti-
which began with the use of the commercially available 1-(S)-
a-
methylbenzylaziridine-2-methanol 6. The route uses key
a
Sharpless asymmetric dihydroxylation reaction of an (E)-aziri-
dine-enoate, derived from 6, and a regioselective aziridine-to-pyr-
rolidinone ring expansion process to generate a key dihydroxylated
pyrrolidine intermediate, which contains the three contiguous ste-
reogenic centers of the target with the correct absolute
configurations.
2. Results and discussion
Our strategy to prepare (+)-lentiginosine 1 is based on the ret-
rosynthetic analysis illustrated in Scheme 1. We envisioned that
the indolizidine ring in the target compound could be formed from
2-butenylpyrrolidine derivative 2 via hydrogenolysis and subse-
quent cyclization. In addition, we believed that a regioselective azi-
ridine ring opening/lactam ring formation sequence starting with
diol 4 would serve as an efficient method to generate the function-
alized pyrrolidine 3, a precursor of 2. Finally, we reasoned that the
anti-diol array in 4 could be readily installed in a highly diastereo-
selective manner via Sharpless asymmetric dihydroxylation of the
(E)-3-(aziridin-2-yl)acrylate 5, a substance directly produced from
chiral aziridine 6.
The preparation of (+)-lentiginosine 1 started with a two-step
synthesis of (E)-3-(aziridin-2-yl)acrylate 5 in 72% yield by using
previously described procedures (Scheme 2).19 Although we
cal properties {1H and 13C NMR, and specific rotation: ½a 1D9:8
¼ þ2:2
ꢀ
OTBS
OTBS
OTBS
OTBS
OH
H
intramolecular
cyclization
C-3 Wittig
HO
homologation
N
OH
N
N
Ph
BnO
Ph
(+)-lentiginosine 1
2
3
Ph
Ph
Ph
regioselective
ring opening
and
Sharpless
OH
Horner-Wadsworth-Emmons
olefination
asymmetric
N
N
N
dihydroxylation
CO2Et
recyclization
CO2Et
OH
H
H
H
OH
4
5
6
Scheme 1. Retrosynthetic analysis of (+)-lentiginosine 1.

H. Yoon et al. / Tetrahedron: Asymmetry 25 (2014) 497–502
499
Ph
Ph
Ph
(COCl)2, DMSO,
TEA
(EtO)2P(O)CH2CO2Et
LHMDS
N
N
N
CO2Et
THF, rt
OH
O
CH2Cl2, - 78 °C
72% (2 steps)
H
H
H
7
5
6
Ph
Ph
AD-mix-α
OH
OH
methane sulfonamide
N
N
CO2Et
CO2Et
t-BuOH, H2O, 0 o
63%
4a / 4b = 11 / 1
C
+
H
H
OH
OH
4a
4b
Scheme 2. Synthesis of diol 4a.
Table 1
Dihydroxylation of (E)-3-(aziridin-2-yl)acrylate 5
Entry
Reagents
Solvent and temperature (°C)
4a/4bc
Yield (%)
1
2
3
4
OsO4, TMEDAa
CH2Cl2, ꢁ78
THF/H2O, 0
t-BuOH/H2O, rt
t-BuOH/H2O, 0
—
N.R.
95d
69e
63e
OsO4b, NMO
3:2
7:1
11:1
AD-mix-
a
a
, methane sulfonamide
, methane sulfonamide
AD-mix-
a
b
c
N,N,N0,N0-Tetramethylethylenediamine.
5 wt % in H2O.
Based on the crude 1H NMR (400 MHz) spectra.
Mixture of 4a and 4b.
d
e
Isolated yield of 4a.
OH
O
OTBS
OTBS
TBSOTf, 2,6-lutidine
AcO
AcO
AcOH, CH2Cl2, rt
OH
4a
N
N
CH2Cl2, 0 o
91%
C
toluene, 90 o
72%
C
Ph
Ph
O
9
8
OTBS
OTBS
OTBS
OTBS
1. (COCl)2, DMSO, TEA
CH2Cl2, -78 o
1. KOH, EtOH
C
HO
N
2. BH3SMe2,THF, 0 o
81% (2 steps)
C
N
2.
Ph
BnO
t-BuOK, THF, 0 o
12
BnO
PPh3Br
Ph
C
3
2
66% (2 steps)
OTBS
OTBS
OTBS
OTBS
H
N
CBr4, PPh3, TEA
Pd(OH)2, H2, cat. TFA
HN
10
CH2Cl2, 0 o
74%
C
MeOH, rt
88%
OH
H
11
OH
3M HCl
OH
N
CH3CN, rt
86%
(+)-lentiginosine 1
Scheme 3. Synthesis of (+)-lentiginosine 1.
(c 0.17, MeOH), lit.10
½
a 2D0
ꢀ
¼ þ2:4 (c 0.41, MeOH)} matched those
was completed in 8.9% overall yield. Key features of the route in-
clude a highly stereoselective aziridine-enoate dihydroxylation
and a regioselective aziridine ring opening/pyrrolidinone forming
cyclization sequence. To the best of our knowledge, the prepara-
tion of (+)-lentiginosine starting from a chiral aziridine has not
been previously described. Considering its efficiency and potential
versatility, the general strategy employed herein should be appli-
cable to the preparation of a wide range of polyhydroxylated pyr-
rolidines and indolizidines.
previously reported.10
3. Conclusion
In the studies described above, we have developed a novel, 12
step route for the highly stereoselective synthesis of (+)-lentigino-
sine, which began with the commercially available aziridine 6 and

500
H. Yoon et al. / Tetrahedron: Asymmetry 25 (2014) 497–502
which it was partitioned between CH2Cl2 (300 mL) and H2O
4. Experimental
4.1. General
(200 mL). The aqueous layer was extracted with CH2Cl2
(100 mL ꢂ 3) and combined organic layer was washed with brine,
dried over MgSO4, filtered through a pad of Celite, and concen-
trated under reduced pressure. The residue was subjected to silica
gel column chromatography with ethyl acetate/hexane (2:1) to
give the title product 4a (2.7 g, 63% yield) as a pale yellow oil; 1H
Reactions were monitored by thin layer chromatography (TLC)
with 0.25 mm E. Merck pre-coated silica gel plates (60 F254). Reac-
tion progress was monitored by TLC analysis using a UV lamp, nin-
hydrin, p-anisaldehyde stain for detection purpose. Purification of
the reaction products was carried out by flash column chromatog-
raphy using Kieselgel 60 Art. 9385 (230–400 mesh). The purity of
all compounds was over 95% and was analyzed with Waters LCMS
system (Waters 2998 Photodiode Array Detector, Waters 3100
Mass Detector, Waters SFO System Fluidics Organizer, Water
2545 Binary Gradient Module, Waters Reagent Manager, Waters
2767 Sample Manager) using SunFireTM C18 column
NMR (400 MHz CDC13):
d 7.36–7.25 (m, 5H), 4.20 (q, 2H,
J = 7.2 Hz), 3.90 (d, 1H, J = 1.2 Hz), 3.76 (br s, 1H), 3.43 (br s, 1H),
2.55 (q, 1H, J = 6.4 Hz), 2.27 (br s, 1H), 2.08 (d, 1H, J = 3.2 Hz),
1.86–1.82 (m, 1H), 1.62 (d, 1H, J = 6.4 Hz), 1.44 (d, 3H, J = 6.4 Hz),
1.25 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz CDC13): d 172.21,
143.76, 128.63, 127.56, 126.72, 71.75, 70.81, 69.53, 61.70, 39.97,
31.52, 22.48, 14.07; ESI-HRMS (m/z): [M+Na]+, calcd for
C
15H21NO4Na, 302.1363; found 302.1356. Diastereomer 4b: 1H
NMR (400 MHz CDCl3): 7.36–7.28 (m, 5H), 4.18 (q, 2H,
d
(4.6 ꢂ 50 mm,
5 lm particle size): solvent gradient = 60% (or
J = 7.2 Hz), 3.97 (d, 1H, J = 2.4 Hz), 3.52 (dd, 1H, J = 2.4 Hz, 6.4 Hz),
3.14 (br s, 1H), 2.55 (q, 1H, J = 6.4 Hz), 2.22 (br s, 1H), 1.95
(d, 1H, J = 3.6 Hz), 1.90–1.86 (m, 1H), 1.56 (d, 1H, J = 6.4 Hz), 1.44
(d, 3H, J = 6.4 Hz), 1.24 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz
CDC13): d 172.16, 143.96, 128.51, 127.40, 126.71, 73.03, 72.19,
69.29, 61.52, 40.07, 31.45, 22.40, 13.95.
95%) A at 0 min, 1% A at 5 min; solvent A = 0.035% TFA in water;
solvent B = 0.035% TFA in MeOH; flow rate: 3.0 (or 2.5) mL/min.
1H NMR and 13C NMR spectra were obtained using a Bruker
400 MHz FT-NMR (400 MHz for 1H, and 100 MHz for 13C) spec-
trometer. Chemical shifts are reported relative to chloroform
(d = 7.26) for 1H NMR and chloroform (d = 77.2) for 13C NMR or
deuterium oxide (d = 4.80) for 1H NMR and deuterium oxide for
13C NMR. Data are reported as br = broad, s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, pent = pentet, dt = double of
triplets, ddd = double of double of doublets. Optical rotations were
measured on a Rudolph Autopol III polarimeter at the wavelength
of sodium D-line (589 nm) at room temperature. Infrared spectra
were measured on FT-IR Nicolet iS10 spectrometer, using KBr
disks. High resolution mass spectra (HRMS) were recorded on a
QTOF mass spectrometer.
4.1.3. ((2S,3S,4R)-3,4-Dihydroxy-5-oxo-1-((R)-1-phenylethyl)pyrr-
olidin-2-yl)methyl acetate 8
To a solution of 4a (1.79 g, 6.4 mmol) in CH2Cl2 (20 mL) was
added acetic acid (5.48 mL, 96 mmol). The mixture was stirred
for 12 h at room temperature (the consumption of 4a was moni-
tored by TLC), diluted with toluene (200 mL), and stirred for 12 h
at 90 °C. The reaction mixture was concentrated under reduced
pressure and partitioned between CH2Cl2 and a saturated NaHCO3
solution. The aqueous layer was extracted with CH2Cl2 and the
combined organic layer was washed with brine, dried over MgSO4,
filtered through a pad of Celite, and concentrated in vacuo. The res-
idue was subjected to silica gel column chromatography with ethyl
acetate/hexane (4:1) to give the title product 8 (1.35 g, 72% yield)
4.1.1. (E)-Ethyl 3-((R)-1-((R)-1-phenylethyl)aziridin-2-yl)acrylate 5
To
a solution of (COCl)2 (4.1 mL, 47.73 mmol) in CH2Cl2
(100 mL) was slowly added DMSO (7 mL, 99.43 mmol) at ꢁ78 °C.
After 30 min, a solution of 6 (7.05 g, 39.77 mmol) in CH2Cl2
(80 mL) was added. After 30 min, NEt3 (22 mL, 119.3 mmol) was
added at ꢁ78 °C then reaction mixture was stirred for 30 min at
0 °C. The mixture was quenched with H2O and then extracted with
CH2Cl2. The combined organic layer was dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. Without further purifi-
cation, to a solution of aldehyde in THF (80 mL) was added triethyl
phosphonoacetate (9.47 mL, 47.73 mmol) at room temperature.
After 10 min at room temperature, LHMDS (47.73 mL, 47.73 mmol,
1 M in THF) was added. The resulting mixture was stirred for 1 h at
room temperature and then quenched with H2O. The mixture was
then extracted with ethyl acetate. The combined organic layer was
dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
Purification by silica gel flash column chromatography with ethyl
acetate/hexane (1:6) provided 7.02 g of 5 in 72% yield (two steps
yield) as a yellow oil; 1H NMR (400 MHz CDC13): d 7.28–7.13 (m,
5H), 6.59 (dd, 1H, J = 7.6 Hz, 16.0 Hz), 5.83 (d, 1H, J = 15.2 Hz),
4.07 (q, 2H, J = 7.2 Hz), 2.48 (q, 1H, J = 6.4 Hz), 1.94–1.90 (m, 2H),
1.72–170 (m, 1H), 1.34 (d, 3H, J = 6.4 Hz), 1.23 (t, 3H, J = 7.2 Hz);
13C NMR (100 MHz CDC13): d 166.38, 148.25, 144.31, 128.57,
127.22, 126.66, 121.92, 70.08, 60.43, 38.77, 37.12, 23.63, 14.39;
ESI-HRMS (m/z): [M+Na]+, calcd for C15H19NO2Na, 268.1308; found
268.1360.
as a pale yellow oil; ½a D24:5
ꢀ
¼ þ7:8 (c 0.20, MeOH), 1H NMR
(400 MHz CDC13): d 7.38–7.26 (m, 5H), 5.41 (q, 1H, J = 7.2 Hz),
4.33 (d, 1H, J = 6.8 Hz), 4.18 (t, 1H, J = 6.8 Hz), 4.03–3.95 (m, 2H),
3.69–3.66 (m, 1H), 1.85 (s, 3H), 1.74 (d, 3H, J = 7.6 Hz); 13C NMR
(100 MHz CDC13):
d 173.34, 170.32, 140.33, 128.39, 127.56,
126.88, 76.17, 73.83, 61.03, 58.97, 49.90, 20.45, 15.81; ESI-HRMS
(m/z): [M+Na]+, calcd for C15H19NO5Na, 316.1155; found 316.1155.
4.1.4. ((2S,3S,4R)-3,4-Bis((tert-butyldimethylsilyl)oxy)-5-oxo-1-
((R)-1-phenylethyl)pyrrolidin-2-yl)methyl acetate 9
To a solution of 8 (1.28 g, 4.4 mmol) in CH2Cl2 (20 mL) was were
added 2,6-lutidine (1.5 mL, 13.1 mmol) and TBSOTf (1.7 mL,
9.6 mmol) at 0 °C. The reaction mixture was warmed to room tem-
perature and stirred for 1 h. The reaction mixture was concen-
trated under reduced pressure and partitioned between CH2Cl2
and H2O. The aqueous layer was extracted with CH2Cl2 and the
combined organic layer was washed with brine, dried over MgSO4,
filtered through a pad of Celite, and concentrated in vacuo. The res-
idue was subjected to silica gel column chromatography with ethyl
acetate/hexane (1:12) to give the title product 9 (2.09 g, 91% yield)
as a colorless oil; 1H NMR (400 MHz CDC13): d 7.36–7.22 (m, 5H),
5.40 (q, 1H, J = 6.8 Hz), 3.96 (d, 1H, J = 1.6 Hz), 3.93 (t, 1H,
J = 1.6 Hz), 3.74 (dd, 1H, J = 8.4 Hz, 11.2 Hz), 3.64 (dd, 1H,
J = 4.0 Hz, 11.2 Hz), 3.56 (qd, 1H, J = 1.6 Hz, 4.4 Hz), 1.89 (s, 3H),
1.64 (d, 3H, J = 7.2 Hz), 0.91 (s, 9H), 0.88 (s, 9H), 0.20 (s, 3H), 0.18
(s, 3H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz CDC13): d
172.70, 170.09, 141.19, 128.41, 127.45, 126.87, 78.07, 74.08,
62.83, 62.64, 49.36, 25.66, 25.60, 20.53, 18.06, 17.85, 15.90,
ꢁ4.49, ꢁ4.69, ꢁ5.01, ꢁ5.06; ESI-HRMS (m/z): [M+Na]+, calcd for
4.1.2. (2R,3S)-Ethyl 2,3-dihydroxy-3-((S)-1-((R)-1 phenylethyl)
aziridin-2-yl)propanoate 4a
To a solution of 5 (3.3 g, 13.3 mmol) in H2O/t-BuOH (60 mL/
60 mL) were added AD-mix-
19.9 mmol) at 0 °C. The reaction mixture was stirred for 24 h and
then washed with a saturated Na2SO3 solution (50 mL ꢂ 3) after
a (33 g), methanesulfonamide (1.9 g,
C27H47NO5Si2Na, 544.2885; found 544.2881.

H. Yoon et al. / Tetrahedron: Asymmetry 25 (2014) 497–502
501
4.1.5. ((2S,3S,4S)-3,4-Bis((tert-butyldimethylsilyl)oxy)-1-((R)-1-
phenylethyl)pyrrolidin-2-yl)methanol 3
4.1.7. 4-((2S,3S,4S)-3,4-Bis((tert-butyldimethylsilyl)oxy)pyrroli-
din-2-yl)butan-1-ol 10
To a solution of 9 (917 mg, 1.76 mmol) in EtOH (5 mL) was
added KOH (200 mg, 3.5 mmol). The reaction mixture was stirred
for 1 h at room temperature and then concentrated under reduced
pressure and partitioned between CH2Cl2 and H2O. The aqueous
layer was extracted with CH2Cl2 and the combined organic layer
was washed with brine, dried over MgSO4, filtered through a pad
of Celite, and concentrated in vacuo. To a solution of crude product
in THF (35 mL) was slowly added BH3SMe2 (0.37 mL, 3.65 mmol) at
0 °C. The reaction mixture was stirred for 2 h at room temperature
and then stirred for an additional 1 h at 70 °C. The reaction mixture
was quenched with EtOH (10 mL) very slowly at 0 °C and concen-
trated under reduced pressure. The reaction mixture was dissolved
in EtOH (35 mL) and stirred for 1 h at 90 °C. The reaction mixture
was diluted with CH2Cl2 and washed with a saturated NaHCO3 solu-
tion. The combined organic layer was dried over MgSO4, filtered
through a pad of Celite, and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography
To a solution of 2 (159 mg, 0.267 mmol) in MeOH (5 mL) was
were added Pd(OH)2 (16 mg) and CF3CO2H (three drops) under a
hydrogen atmosphere (balloon) at room temperature. The reaction
mixture was stirred for 24 h at room temperature and filtered
through a pad of Celite and concentrated in vacuo to give the crude
product, which was purified by silica gel flash column chromatog-
raphy with MeOH/CH2Cl2 (5:95) to give the title compound 10
(93 mg, 88%) as a yellow oil; 1H NMR (400 MHz CDC13): d 3.90–
3.89 (m, 1H), 3.62–3.60 (m, 3H), 3.00 (dd, 1H, J = 4.0 Hz, 12.0 Hz),
2.87–2.77 (m, 4H), 1.64ꢁ1.43 (m, 6H), 0.85 (s, 9H), 0.85 (s, 9H),
0.05 (s, 3H), 0.04 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR
(100 MHz CDC13): d 83.79, 79.53, 67.40, 62.23, 53.45, 33.19,
32.42, 25.75, 23.30, 17.87, ꢁ4.42, ꢁ4.56, ꢁ4.64, ꢁ4.70; ESI-HRMS
(m/z): [M+H]+, calcd for C20H46NO3Si2, 404.3011; found 404.3005.
4.1.8. (1S,2S,8aS)-1,2-Bis((tert-butyldimethylsilyl)oxy)octahydro-
indolizine 11
with ethyl acetate/hexane (1:9) to give the title product
3
(664 mg, 81% yield) as a colorless oil; ½a D24:5
¼ þ29:6 (c 0.25, CHCl3),
ꢀ
To a solution of 10 (156 mg, 0.386 mmol) in CH2Cl2 (12 mL) was
added CBr4 (320 mg, 0.965 mmol) and cooled to 0 °C. Next, PPh3
(354 mg, 1.35 mmol), and NEt3 (0.27 mL, 1.93 mmol) were dis-
solved in CH2Cl2 (8 mL) and then added to the substrate mixture
by cannula. The reaction mixture was stirred for 6 h at room tem-
perature. The mixture was quenched with 7 M NH3ꢃMeOH and par-
titioned with CH2Cl2 and H2O. The aqueous layer was extracted
with CH2Cl2 and the combined organic layer was washed with
brine, dried over MgSO4, filtered through a pad of Celite, and con-
centrated in vacuo. The residue was subjected to silica gel column
chromatography with ethyl acetate/hexane (1:9) to give the title
product 11 (110 mg, 74% yield) as a yellow solid; 1H NMR
(400 MHz CDC13): d 3.96 (ddd, 1H, J = 2.0 Hz, 4.0 Hz, 6.4 Hz), 3.70
(dd, 1H, J = 4.0 Hz, 8.4 Hz), 2.89 (d, 1H, J = 10.8 Hz), 2.83 (dd, 1H,
J = 2.0 Hz, 10.0 Hz), 2.51 (dd, 1H, J = 8.0 Hz, 9.6 Hz), 1.92ꢁ1.72 (m,
4H), 1.57ꢁ1.53 (m, 2H), 1.26ꢁ1.12 (m, 2H), 0.87 (s, 18H), 0.06 (s,
3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz
CDC13): d 85.20, 78.04, 68.33, 62.14, 53.41, 28.76, 25.98, 25.86,
24.92, 23.95, 17.94, 17.90, ꢁ4.07, ꢁ4.24, ꢁ4.27, ꢁ4.67; ESI-HRMS
(m/z): [M+H]+, calcd for C20H44NO2Si2, 386.2905; found 386.2957.
1H NMR (400 MHz CDC13): d 7.32–7.25 (m, 5H), 3.98 (t, 1H,
J = 1.6 Hz), 3.78 (q, 1H, J = 6.8 Hz), 3.76–3.74 (m, 1H), 3.71 (dd, 1H,
J = 3.6 Hz, 10.8 Hz), 3.63 (dd, 1H, J = 2.8 Hz, 10.8 Hz), 2.84–2.82
(m, 1H), 2.77–2.71 (m, 2H), 1.41 (d, 3H, J = 6.8 Hz), 0.88 (s, 9H),
0.83 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H); 13
C
NMR (100 MHz CDC13): d 143.43, 128.17, 127.54, 126.90, 81.54,
77.21 (overlapped with CDCl3), 69.92, 61.85, 61.52, 56.80, 25.72,
25.71, 22.23, 17.93, 17.79, ꢁ4.59, ꢁ4.70, ꢁ4.79, ꢁ4.83; ESI-HRMS
(m/z): [M+Na]+, calcd for C25H48NO3Si2Na, 466.3167; found
466.3162.
4.1.6. (2S,3S,4S)-2-(4-(Benzyloxy)but-1-en-1-yl)-3,4-bis((tert-butyl-
dimethylsilyl)oxy)-1-((R)-1-phenylethyl)pyrrolidine 2
To a solution of (COCl)2 (0.5 mL, 5.76 mmol) in CH2Cl2 (24 mL)
was slowly added DMSO (0.85 mL, 12 mmol) at ꢁ78 °C. After
30 min, a solution of 3 (2.23 g, 4.8 mmol) in CH2Cl2 (24 mL) was
added. After 30 min, NEt3 (28 mL, 20.16 mmol) was added at
ꢁ78 °C then the reaction mixture was stirred for 30 min at 0 °C.
The reaction mixture was quenched with H2O and then extracted
with CH2Cl2. The combined organic layer was dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. To a solution of 12
(7.1 g, 14.4 mmol) in THF (24 mL) was slowly added potassium
tert-butoxide solution (9.6 mL, 9.6 mmol, 1 M in THF) at 0 °C. After
removing the ice bath, the resulting mixture was stirred for 1 h.
When an orange color appeared, a solution of the crude aldehyde
in THF (24 mL) was slowly added by cannula at 0 °C. The resulting
mixture was stirred for 1 h at room temperature and then quenched
with saturated NH4Cl solution. The reaction mixture was then ex-
tracted with ethyl acetate. The combined organic layer was dried
over anhydrous MgSO4, filtered, and concentrated in vacuo. Purifi-
cation by silica gel flash column chromatography with ethyl ace-
tate/hexane (1:30) provided 1.89 g of 2 in 66% yield (two steps
4.1.9. (1S,2S,8aS)-Octahydroindolizine-1,2-diol, (+)-lentiginosine
1
To a solution of 11 (20 mg, 0.051 mmol) in acetonitrile (0.4 mL)
was added 3 M HCl (0.4 mL) at room temperature. The reaction
mixture was stirred for 4 h and then neutralized by the addition
of anhydrous Na2CO3 at 0 °C. The reaction mixture was filtered
through a pad of Celite and concentrated under reduced pressure.
The resulting residue was dissolved in H2O and extracted several
times with isopropyl alcohol/CHCl3 (1:4). The combined organic
layer was dried over MgSO4, filtered through a pad of Celite, and
concentrated under reduced pressure. The residue was subjected
to silica gel column chromatography with CH2Cl2/MeOH/NH4OH
(41:8:1) to give the title compound 1, (+)-lentiginosine (6.9 mg,
86%) as a white solid; Rf (CH2Cl2/MeOH/NH4OH = 41:8:1) = 0.4;
yield) as a colorless oil; ½a D24:5
ꢀ
¼ þ67:6 (c 0.25, CHCl3), 1H NMR
(400 MHz CDC13): d 7.31–7.15 (m, 10H), 5.53–5.48 (m, 2H), 4.47
(s, 2H), 3.82 (pent, 1H, J = 3.2 Hz), 3.76 (q, 1H, J = 6.8 Hz), 3.70 (dd,
1H, J = 3.2 Hz, 4.8 Hz), 3.47–3.38 (m, 2H), 3.16 (dd, 1H, J = 4.8 Hz,
8.4 Hz), 2.78 (dd, 1H, J = 6.4 Hz, 10 Hz), 2.68 (dd, 1H, J = 3.2 Hz,
10 Hz), 2.34–2.20 (m, 2H), 1.31 (d, 3H, J = 7.2 Hz), 0.85 (s, 9H),
0.80 (s, 9H), ꢁ0.02 (s, 6H), ꢁ0.03 (s, 3H), ꢁ0.04 (s, 3H); 13C NMR
½
a 1D9:8
ꢀ
¼ þ2:2 (c 0.17, MeOH); IR (KBr, cmꢁ1):
v = 3351, 2933,
2853, 1141, 1045; 1H NMR (400 MHz D2O): d 4.01–3.99 (m, 1H),
3.58 (dd, 1H, J = 4.0 Hz, 8.8 Hz), 2.88 (d, 1H, J = 11.2 Hz), 2.77 (d,
1H, J = 11.2 Hz), 2.58 (dd, 1H, J = 7.6 Hz, 11.2 Hz), 2.00 (dt, 1H,
J = 2.4 Hz, 12.0 Hz), 1.92–1.83 (m, 2H), 1.74–1.73 (m, 1H), 1.57 (d,
1H, J = 13.2 Hz), 1.43–1.33 (m, 1H), 1.23–1.13 (m, 2H), 13C NMR
(100 MHz D2O): d 82.73, 75.47, 68.41, 60.06, 52.49, 27.38, 23.80,
22.87; ESI-HRMS (m/z): [M+H]+, calcd for C8H16NO2, 158.1176;
found 158.1193.
(100 MHz CDC13):
d 142.09, 138.39, 132.66, 128.19, 127.86,
127.77, 127.46, 127.35, 126.55, 84.65, 77.74, 72.76, 69.73, 64.85,
59.12, 54.64, 28.48, 25.74, 25.69, 21.29, 17.78, 17.67, ꢁ4.42, ꢁ4.50,
ꢁ4.53, ꢁ4.75; ESI-HRMS (m/z): [M+H]+, calcd for C35H58NO3Si2,
596.3950 found 596.3963.

502
H. Yoon et al. / Tetrahedron: Asymmetry 25 (2014) 497–502
9. (a) Feng, Z. X.; Zhou, W. S. Tetrahedron Lett. 2003, 44, 497–498; (b) Gurjar, M. K.;
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This research was supported by Korea Institute of Science and
Technology and a Grant (NRF-2011-0028676) from the creative/
challenging research program of National Research Foundation of
Korea and a Grant (D33400) from Korea Basic Science Institute
and a Grant (A111345) from the Korea Health Technology R&D
Project, Ministry of Health & Welfare, Republic of Korea.
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