An efficient synthesis of functionalized pyrrolidines and 5-epi-hyacinthacine A4 from D-glucose

Article abstract of DOI:10.1055/s-2007-966022

The two partially protected pyrrolidines (2R,3S,AR,5R)-and (2R,3S,4R,5R)-3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-[(tert- butyldimethylsiloxy)methyl]pyrrolidine were synthesized from D-glucose as precursor in the stereoselective synthesis of hyacinthaci

Full text of DOI:10.1055/s-2007-966022

PAPER
1359
An Efficient Synthesis of Functionalized Pyrrolidines and 5-epi-Hyacinthacine
A4 from D-Glucose
S
ynthesis of Fu
i
nctiona
n
lized Pyrroli
g
dines and 5-epi-H
y
Z
acinthacine
A
4hou, Jie Chen, Xiao-Ping Cao*
State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou,
Gansu 730000, P. R. of China
Fax +86(931)8912582; E-mail: caoxplzu@163.com
Received 19 January 2007; revised 21 February 2007
Owing to their remarkable biological properties, polyhy-
Abstract: The two partially protected pyrrolidines (2R,3S,4R,5S)-
droxylated pyrrolizidine alkaloids have attracted consid-
erable attention in organic synthesis. Many strategies have
been used for the stereocontrolled synthesis of polyhy-
and (2R,3S,4R,5R)-3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-
[(tert-butyldimethylsiloxy)methyl]pyrrolidine were synthesized
from D-glucose as precursor in the stereoselective synthesis of hya-
cinthacines. The key strategies were the ring opening of the sugar droxylated pyrrolizidine alkaloids, such as using starting
materials from the chiral pool (e.g., carbohydrates,6 amino
epoxide with sodium azide to convert the configuration at C-2 and
acids,7 castanospermine8), cycloaddition reactions,9
C-3 of D-glucose and simultaneous reduction and intramolecular
cyclization. 5-epi-Hyacinthacine A4 was synthesized from the
chemoenzymatic approaches,10 ring-closing metathesis
(2R,3S,4R,5S)-pyrrolidine by Wittig reaction and cyclization.
reactions,11 and other approaches.12 When all the synthe-
Key words: azasugars, chiral pool, hyacinthacine, pyrrolidines,
ring opening
ses are compared, carbohydrate-based syntheses have to
date been one of the most popular and efficient strategies.
Recently, Izquierdo and co-workers prepared a series of
hyacinthacines by reductive cyclization of the corre-
sponding pyrrolidines,6d,e,g–i which were synthesized from
D-fructose as the chiral starting material.13 Other synthetic
strategies for accessing pyrrolidines have also been pub-
lished.14
Polyhydroxylated pyrrolizidines possessing a hydroxy-
methyl substituent at C-3 make up a new class of pyrroliz-
idine alkaloids with intriguing structures and remarkable
biological properties (Figure 1).1 The first examples of
this family were alexine isolated from Alexal leiopetala,
and australine isolated from the seeds of Castanospermum
australe,2 both of them exhibiting promising biological
activity (e.g. antiviral and anti-HIV activity).3 Recently, a
series of hyacinthacines was isolated from Hyacinthaceae
plants (Hyacinthoides nonscripta, Muscari armeniacum,
Scilla sibirica, and Scilla peruviana) by Asano and co-
workers.4 Many of these alkaloids display potent glycosi-
dase inhibitory activity, which makes them potential drug
candidates against viral infections, cancer, and diabetes.5
Here we report the synthesis of two key intermediates for
the stereoselective synthesis of hyacinthacines, namely
the preparation of (2R,3S,4R,5S)- and (2R,3S,4R,5R)-3,4-
bis(benzyloxy)-2-[(benzyloxy)methyl]-5-[(tert-butyldi-
methylsiloxy)methyl]pyrrolidine (1 and 2, respectively;
Scheme 1) from D-glucose. The synthetic strategy is out-
lined in Scheme 1; pyrrolidine 1, which holds the stereo-
chemistry at C-2, C-3, C-4, and C-5 belonging to the
right-hand side of hyacinthacine A4, as shown in
Scheme 1, is prepared from azide 3 by simultaneous re-
duction and cyclization reactions. Thus, carbon-chain
lengthening at C-2¢ (the original C-1 of glucose) by a suit-
able functionalized two-carbon-atom fragment, followed
by further cyclization, should lead to hyacinthacine A4.
Compound 3 is prepared stepwise from the sugar epoxide
5. The configuration at C-2 of 5 is converted by a ring-
opening strategy applied to sugar epoxide 5 to be suitable
for hyacinthacines. Compound 5 is easily prepared from
D-glucose, which is available as source of chirality and
functionalization. Based on pyrrolidine 1, 5-epi-hya-
cinthacine A4 could be synthesized.
HO
OH
HO
OH
H
N
H
1
7
6
7a
2
3
OH
OH
N
5
OH
OH
alexine
australine
OH
HO
OH
H
N
H
N
OH
OH
OH
hyacinthacine A4
OH
hyacinthacine B5
The other key intermediate 2 could be used as the starting
material for many hyacinthacines,13c by the same strategy
described above (Scheme 1). Because the configuration at
C-5 (the original C-5 of glucose) of 2 and 1 differs, 2
needed to be prepared from azide 4, by the same approach
described for the preparation of 1. Azide 4 is also prepared
from 5, but with inversion of the configuration at C-5 of
glucose.
Figure 1 Polyhydroxylated pyrrolizidines
SYNTHESIS 2007, No. 9, pp 1359–1365
x
x
.
x
x
.2
0
0
7
Advanced online publication: 18.04.2007
DOI: 10.1055/s-2007-966022; Art ID: F01607SS
© Georg Thieme Verlag Stuttgart · New York

1360
L. Zhou et al.
PAPER
OH
H
N
BnO
OTBS
N3
H
N
BnO
BnO
5
5
2
OMs
5'
2'
OH
OTBS
5
BnO
OBn
OBn
OH
5-epi-hyacinthacine A4
O
Ph
5
1
3
O
O
STol
inversion
O
R1
OH
H
N
5
BnO
OTBS
N3
BnO
BnO
H
N
R2
OH
5
OTBS
OH
OBn
D-glucose
R3
BnO
OBn
OH
hyacinthacines, ref. 13c
2
4
Scheme 1 Retrosynthetic analysis of hyacinthacines
Sugar epoxide 5 was prepared from D-glucose by a pub- 11 was activated with methanesulfonyl chloride in pyri-
lished procedure15 (Scheme 2). Treatment of 5 with sodi- dine, and this afforded mesylate 3 in 97% yield
um azide in the presence of ammonium chloride in (Scheme 2). Simultaneous reduction and cyclization of 3
dimethyl sulfoxide at 85 °C gave azido sugar 6 as the sin- with hydrogen (1 bar) in the presence of palladium on car-
gle isomer (by NMR) in 97% yield, and the configuration bon and triethylamine in tetrahydrofuran produced the
at C-2 of 5 was now established. Deprotection of 4,6-O- key intermediate pyrrolidine 1 as a single isomer in 95%
benzylidene of 6 with p-toluenesulfonic acid produced 7 yield and with the correct configuration at C-5, as identi-
in 96% yield, with the 4,5,6-trihydroxy groups exposed fied by 1D and 2D NMR spectroscopy.
(Scheme 2). Benzylation of 7 with benzyl bromide in the
presence of sodium hydride in anhydrous N,N-dimethyl-
formamide gave compound 8 in 96% yield. Hydrolysis of
8 with N-bromosuccinimide in an acetone–water mixture
For the preparation of key intermediate 2 from 5, a double
inversion (retention) of the configuration at C-5 is re-
quired. Normally, inversion of configuration by Mitsuno-
bu reaction is not suitable here for the azido group. Wong
(5:1) at reflux for 48 hours gave hemiacetal 9 in 94% yield
and co-workers have studied a similar problem,16 and
found that the steric effect of the tert-butyldimethylsilyl
group resulted in poor selectivity when azidoketone 12
was cyclized directly by intramolecular reductive amina-
tion (Scheme 3). However, reduction of this type of ke-
tone gave a Felkin–Ahn model product,16b which had the
configuration we desired. So the strategy of reducing the
1
as a mixture (b/a = 3:1, by H NMR). The mixture does
not need to be separated, and can be used in the next step.
Reduction of compound 9 with sodium borohydride in
methanol produced diol 10 in 91% yield (Scheme 2). Se-
lective protection of the primary hydroxy group of 10 with
tert-butyldimethylsilyl chloride in pyridine in the pres-
ence of a catalytic amount of 4-(N,N-dimethylamino)pyri-
dine gave alcohol 11 in 95% yield. The hydroxy group in
corresponding ketone to prepare
(Scheme 3).
4 was adopted
N3
O
O
O
Ph
Ph
a
c
O
b
D-glucose
O
O
STol
STol
O
5
OH
6
N3
O
N3
O
HO
BnO
N3
O
BnO
BnO
e
f
d
HO
BnO
STol
STol
OH
OH
OBn
OBn
7
8
9
N3
OH
N3
OH
N3
OMs
BnO
BnO
BnO
BnO
BnO
g
i
h
1
BnO
OH
OTBS
OTBS
OBn
10
OBn
11
OBn
3
Scheme 2 Synthesis of pyrrolidine 1. Reagents and conditions: (a) Lit.15; (b) NaN3, NH4Cl, DMSO, 85 °C, 5 h, 97%; (c) TsOH, MeOH, r.t.,
3 h, 96%; (d) NaH, BnBr, DMF, 96%; (e) NBS, acetone–H2O (5:1), reflux, 48 h, 94%; (f) NaBH4, MeOH, 91%; (g) TBSCl, py, DMAP, 95%;
(h) MsCl, py, 97%; (i) 10% Pd/C, H2 (1 bar), Et3N, THF, 95%.
Synthesis 2007, No. 9, 1359–1365 © Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Pyrrolidines and 5-epi-Hyacinthacine A4
1361
Thus, the secondary hydroxy group of 11 was oxidized genation of 15 at one bar gave saturated ketone 16, which
with the Dess–Martin periodinane in dichloromethane to also appeared as a single rotamer in the NMR spectra of
produce azidoketone 12 in 91% yield (Scheme 3). Then an aliquot. This intermediate was not isolated, but treated
ketone 12 was reduced with sodium borohydride in meth- immediately with concentrated hydrochloric acid to re-
anol at 0 °C to near completion, with a Felkin–Ahn-type move the Boc group; cyclization and neutralization [Am-
addition affording mainly the secondary alcohol 4 with berlite IRA-400 (OH–)] followed. This yielded enamine
the inversion at C-5 for the first time. The second inver- 17, and a second catalytic hydrogenation of 17 at 4 bar for
sion at C-5 was achieved as follows: the hydroxy groups three days afforded 5-epi-hyacinthacine A4 (18) in 41%
of compounds 4 and 11 in the mixture were activated as yield from 15 (Scheme 4).
mesylates, and then reduction and cyclization by the same
The stereochemistry of the new C-5 stereogenic center in
procedures used for preparation of 1 gave a mixture of the
18 was established on the basis of NOE experiments. As
desired isomer 2 as the major product (69% yield) and the
shown in Figure 2, the NOE effects between H-9 and H-
8, H-1 and H-2, and H-1 and H-3 indicated that H-1, H-2,
H-3, and H-5 are on the same side of the molecule. Thus,
minor isomer 1 (22% yield) (Scheme 3), which can be
separated easily by flash chromatography.
Compounds 1 and 2 differ in their configuration at C-5, the configuration at C-5 is R. The highly stereoselective
and in their 13C NMR spectra the biggest differences are formation of 18 can be attributed to the particular shape of
in the chemical shifts of C-5 itself and around it; the chem- 17, where the a-face is blocked, and the b-face is favored
ical shift difference Dd is 1–2.4 for C-2, C-2¢, C-4, C-5, for hydrogen addition.
1
and C-5¢ (see Scheme 1 for numbering). The H NMR
O
OH
spectra of the two diastereomers 1 and 2 differ mainly
with regard to the chemical shifts of the protons at C-3 and
C-4; the signal for H-4 shifts upfield owing to the trans
configuration of H-4 and H-5 in compound 2, so that the
signals of H-3 and H-4 are separated, whereas the signals
for H-3 and H-4 overlap for 1 with its cis configuration of
H-4 and H-5.
OBn
OBn
H
N
H
N
a
b
c
1
OBn
OBn
Boc
Boc
OBn
OBn
13
14
O
OBn
OBn
H
N
H
N3
O
BnO
BnO
d
OBn
OBn
a
b
11
N
O
OTBS
Boc
Boc
OBn
OBn
OBn
OBn
15
16
12
N3
BnO
c
OBn
OH
5
11
+
2 + 1
H
H
BnO
4
1
3
7a
OTBS
7
OH
OBn
2
e
f
6
9
OH
N
N
5
4
8
OBn
OH
Scheme 3 Synthesis of pyrrolidine 2. Reagents and conditions: (a)
DMP, CH2Cl2, 91%; (b) NaBH4, MeOH, 0 °C, 2 h, 99%; (c) i. MsCl,
py; ii. 10% Pd/C, H2 (1 bar), Et3N, THF, 2 (69%, two steps), 1 (22%,
two steps).
17
18
5-epi-hyacinthacine A4
Scheme 4 Synthesis of 5-epi-hyacinthacine A4. Reagents and con-
ditions: (a) i. Boc2O, Et3N, CH2Cl2, r.t.; ii. TBAF·3H2O, THF, r.t.,
95% (two steps); (b) (COCl)2, DMSO, Et3N, –78 °C, 94%; (c)
Pyrrolidines 1 and 2 are potentially excellent and versatile Ph3P=CHCOMe, toluene, reflux, 71%; (d) 10% Pd/C, H2 (1 bar),
MeOH; (e) HCl, then Amberlite IRA-400 (OH–); (f) 10% Pd/C, H2 (4
bar), MeOH, 3 d, 41% (from 15).
key intermediates for the enantiosynthesis of polyhydrox-
ylated pyrrolizidines. Here we describe our synthesis,
from 1, of 18, one stereoisomer of hyacinthacine A4
(Scheme 4). Protection of the secondary amine group of 1
H1
H
H
H3
with di-tert-butyl dicarbonate was followed by removal of
the tert-butyldimethylsilyl group with tetrabutylammoni-
um fluoride to give alcohol 13 in 95% yield (Scheme 4).
Swern oxidation of alcohol 13 gave aldehyde 14 in 94%
yield.17 Subsequent Wittig reaction of aldehyde 14 with 1-
triphenylphosphoranylidenepropan-2-one afforded exclu-
sively the E configuration (J = 16.5 Hz) of unsaturated ke-
tone 15 in 71% yield (Scheme 4). For N-acylpyrrolidines,
there are always rotameric forms,18 but the NMR spectra
of compounds 13, 14, and 15 showed only single rota-
mers; this could be due to the all-cis configuration of the
substituted groups of these pyrrolidines. Catalytic hydro-
favored
OH
H2
OBn
OBn
N
N
9CH3
8
OH
OH
BnO
18
17
Figure 2 NOE interactions of 18 and hydrogenation pathway of in-
termediate 17
In conclusion, two partially protected pyrrolidines 1 and 2
were synthesized from the readily available starting mate-
rial D-glucose in high yields and with high stereoselectiv-
ity. The configurations at C-2, C-3, and C-5 of glucose
Synthesis 2007, No. 9, 1359–1365 © Thieme Stuttgart · New York

1362
L. Zhou et al.
PAPER
1H NMR (300 MHz, acetone-d6): d = 2.29 (s, 3 H, CH3), 3.14 (br s,
2 H, 2 × OH), 3.37–3.85 (m, 4 H), 3.92 (dd, J = 3.0, 1.5 Hz, 1 H),
4.18 (t, J = 3.0 Hz, 1 H), 4.77 (br s, 1 H, OH), 5.29 (d, J = 1.5 Hz, 1
H, H-1), 7.14 (d, J = 8.4 Hz, 2 H, ArH), 7.40 (d, J = 8.4 Hz, 2 H,
ArH).
13C NMR (100 MHz, acetone-d6): d = 20.6 (p), 62.6 (s, C-6), 64.9
(t, C-2), 66.2 (t, C-3), 70.3 (t, C-5), 78.1 (t, C-4), 84.4 (t, C-1), 130.2
(t), 131.0 (t), 132.0 (q), 137.5 (q).
were converted successfully during the synthesis of com-
pound 1 by the strategy of ring opening of the sugar ep-
oxide and simultaneous reduction, as well as
intramolecular cyclization. In the synthesis of compound
2, only the configurations at C-2 and C-3 of glucose were
converted by the same strategy, and a double inversion
(retention) at C-5 was achieved. The synthetic routes were
facile and all of the reactions can be performed on large
scale. Compounds 1 and 2 are very useful precursors for
the stereoselective synthesis of hyacinthacines. 5-epi-Hy-
acinthacine A4 was then synthesized from pyrrolidine 1.
This synthetic strategy provided a useful method that can
be applied to a number of pyrrolidines as precursors for
the synthesis of polyhydroxylated pyrrolizidines.
HRMS (ESI): m/z calcd for C13H21N4O4S [M + NH4]+: 329.1278;
found: 329.1273.
p-Tolyl 2-Deoxy-2-azido-3,4,6-tri-O-benzyl-1-thio-b-D-altro-
pyranoside (8)
To a stirred soln of 7 (1.55 g, 5.0 mmol) in anhyd DMF (30 mL) was
added NaH (1.09 g, 25.0 mmol) at 0 °C under argon, and then BnBr
(2.75 mL, 23.0 mmol) was added dropwise. The mixture was stirred
overnight at r.t. The reaction was quenched with ice and the mixture
was extracted with EtOAc (3 × 60 mL). The organic extracts were
washed with H2O (3 × 50 mL) and brine (80 mL), dried (Na2SO4),
filtered, and concentrated in vacuo. Flash chromatography of the
residue (silica gel, PE–EtOAc, 8:1) gave 8 as a colorless oil.
Melting points were measured on an XT-4 apparatus. The optical
rotation was measured with a TE 342 polarimeter. 1H and 13C NMR
spectra were recorded on Mercury Plus-400 and Mercury Plus-300
spectrometers. In the 13C NMR spectra, the following notation is
used: p = 1° C, s = 2° C, t = 3° C, q = 4° C. IR spectra were recorded
on a Nicolet AVATAR 360 FT-IR spectrophotometer. MS and
HRMS were carried out on HP-5988A and Bruker Daltonics APEX
II 47e mass spectrometers, respectively. Anhydrous reactions were
carried out under argon atmosphere and freshly dried solvents were
used. PE (bp 60–90 °C) was used. Column chromatography was
generally performed on silica gel (200–300 mesh) and TLC on sili-
ca gel GF254 plates. Compound 5 was prepared from D-glucose by a
literature procedure.15 The NMR data of 5 were identical to that re-
ported previously.15b
Yield: 2.79 g (96%); [a]D16 –2 (c 1.0, CHCl3).
IR (KBr): 3362, 2920, 2104 (vs, N3), 1453, 1078, 736, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.27 (s, 3 H, CH3), 3.69 (dd,
J = 9.9, 5.7 Hz, 1 H, H-6), 3.77–3.81 (m, 3 H, H-2, 4, 6¢), 3.91 (t,
J = 3.0 Hz, 1 H, H-3), 4.05 (ddd, J = 9.9, 5.7, 1.8 Hz, 1 H, H-5), 4.48
(d, J = 11.7 Hz, 1 H, CH2Ph), 4.52 (d, J = 12.0 Hz, 1 H, CH2Ph),
4.53 (d, J = 12.0 Hz, 2 H, CH2Ph), 4.61 (d, J = 11.7 Hz, 1 H,
CH2Ph), 4.71 (d, J = 11.7 Hz, 1 H, CH2Ph), 5.21 (d, J = 1.2 Hz, 1 H,
H-1), 7.02 (d, J = 8.4 Hz, 2 H, ArH), 7.18–7.34 (m, 15 H, ArH),
7.40 (d, J = 8.4 Hz, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 21.0 (p), 63.7 (t, C-2), 69.6 (s),
72.1 (s), 72.4 (t), 73.4 (s), 74.4 (t), 76.1 (t), 84.1 (t, C-1), 127.3 (t),
127.6 (t), 127.8 (t), 128.0 (t), 128.1 (t), 128.4 (t), 129.6 (t), 130.5 (q),
131.5 (t), 137.5 (t), 137.6 (q), 138.4 (q).
p-Tolyl 2-Deoxy-2-azido-4,6-O-benzylidene-1-thio-b-D-altro-
pyranoside (6)
NaN3 (6.50 g, 100.0 mmol) and NH4Cl (2.68 g, 50.1 mmol) were
added in one portion to a stirred soln of 5 (3.56 g, 10.0 mmol) in
DMSO (50 mL). The mixture was heated to 85 °C and stirred for 5
h. The reaction was quenched with H2O (100 mL) and the mixture
was extracted with EtOAc (3 × 100 mL). The organic extracts were
washed with brine (80 mL), dried (Na2SO4), filtered, and concen-
trated in vacuo. Flash chromatography of the residue (silica gel,
PE–EtOAc, 5:1) gave 6 as a colorless oil.
Yield: 3.87 g (97%); [a]D16 –2 (c 1.0, CHCl3).
IR (KBr): 3459, 2919, 2109 (vs, N3), 1384, 1069, 759, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.33 (s, 3 H, CH3), 2.88 (s, 1 H,
OH), 3.74–3.78 (m, 2 H, H-2, 5), 3.79–3.88 (m, 2 H, H-4, 6), 4.06
(m, 1 H, H-3), 4.26 (dd, J = 9.9, 3.0 Hz, 1 H, H-6¢), 5.18 (d, J = 1.8
Hz, 1 H, H-1), 5.56 (s, 1 H, OCHO), 7.12 (d, J = 8.8 Hz, 2 H, ArH),
7.36–7.47 (m, 7 H, ArH).
HRMS (ESI): m/z calcd for C34H39N4O4S [M + NH4]+: 599.2687;
found: 599.2680.
Alcohol 9
To a stirred soln of 8 (3.20 g, 5.5 mmol) in acetone–H2O (5:1, 60
mL) was added NBS (1.95 g, 11.0 mmol) in one portion. The mix-
ture was stirred for 48 h under reflux, and then two portions of NBS
(1 g) was added. The mixture was poured into sat. NaHCO3 soln (50
mL) and extracted with EtOAc (3 × 100 mL). The organic extracts
were washed with brine (100 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. Flash chromatography of the residue (silica
gel, PE–EtOAc, 5:1) gave 9 as an a/b configuration mixture, which
did not need to be separated, and could be used as is in the next step.
Yield: 2.46 g (94%); b/a = 3:1 (by 1H NMR).
MS (ESI): m/z for C27H29N3O5Na [M + Na]+ found: 498.
13C NMR (75 MHz, CDCl3): d = 21.0 (p), 65.3 (t, C-2), 66.5 (t, C-
3), 68.0 (t, C-5), 68.6 (s, C-6), 76.0 (t, C-4), 84.9 (t, C-1), 102.0 (t),
126.1 (t), 128.3 (t), 129.3 (t), 129.8 (t, q, overlapping), 132.0 (t),
136.7 (q), 138.0 (q).
HRMS (ESI): m/z calcd for C20H22N3O4S [M + H]+: 400.1326;
found: 400.1323.
2-Deoxy-2-azido-3,4,6-tri-O-benzyl-D-altritol (10)
To a stirred soln of 9 (2.40 g, 5.1 mmol) in anhyd MeOH (50 mL)
was added NaBH4 (1.94 g, 5.1 mmol) in one portion at 0 °C under
argon. The mixture was stirred at 0 °C for 10 min and then at r.t. for
1 h. NaBH4 was added portionwise until the starting material had
disappeared completely. The mixture was then cooled to 0 °C and
quenched by addition of glacial AcOH (4 mL). The solvent was re-
moved in vacuo. Flash chromatography of the residue (silica gel,
PE–EtOAc, 2:1) gave 10 as a colorless solid.
p-Tolyl 2-Deoxy-2-azido-1-thio-b-D-altropyranoside (7)
To a stirred soln of 6 (2.00 g, 5.0 mmol) in MeOH (30 mL) was add-
ed TsOH (516 mg, 3.0 mmol). The mixture was stirred for 3 h at r.t.
The reaction was quenched with Et3N (2.0 mL) and the solvent was
removed in vacuo. Flash chromatography of the residue (silica gel,
PE–EtOAc, 1:2) gave 7 as a colorless solid.
Yield: 1.50 g (96%); mp 102–104 °C; [a]D16 –42 (c 1.0, CHCl3).
IR (KBr): 3405, 3289, 2107 (vs, N3), 1274, 1057, 969, 753 cm–1.
Yield: 2.21 g (91%); mp 61–63 °C; [a]D16 +40 (c 1.0, CHCl3).
IR (KBr): 3411, 2922, 2101 (s, N3), 1453, 1073, 738, 698 cm–1.
Synthesis 2007, No. 9, 1359–1365 © Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Pyrrolidines and 5-epi-Hyacinthacine A4
1363
1H NMR (300 MHz, CDCl3): d = 2.84 (br s, 2 H, 2 × OH), 3.53 (dd,
J = 9.9, 5.7 Hz, 1 H), 3.64 (dd, J = 9.9, 3.0 Hz, 1 H), 3.70 (d, J = 4.8
Hz, 2 H), 3.75–3.82 (m, 2 H), 3.95 (t, J = 3.6 Hz, 1 H), 4.03 (td,
J = 6.6, 2.4 Hz, 1 H), 4.44 (d, J = 12.9 Hz, 1 H), 4.47 (d, J = 12.9
Hz, 1 H), 4.54 (d, J = 11.4 Hz, 1 H), 4.63 (d, J = 11.1 Hz, 1 H), 4.70
(d, J = 11.4 Hz, 1 H), 4.72 (d, J = 11.1 Hz, 1 H), 7.22–7.34 (m, 15
H).
(2R,3S,4R,5S)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-5-
[(tert-butyldimethylsiloxy)methyl]pyrrolidine (1)
To a soln of 3 (100 mg, 0.15 mmol) in THF (5 mL) was added 10%
Pd/C (10 mg) and Et3N (0.1 mL, 7.2 mmol). The mixture was stirred
under H2 (1 bar) at r.t. overnight. The mixture was filtered through
Celite and concentrated in vacuo. Flash chromatography of the res-
idue (silica gel, PE–EtOAc, 1:1) gave 1 as yellowish oil.
13C NMR (75 MHz, CDCl3): d = 62.0 (s, C-1), 64.3 (t, C-2), 70.2 (t,
C-5), 71.1 (s, C-6), 73.3 (t), 73.6 (t), 73.9 (t), 79.0 (t, C-3,4, overlap-
ping), 127.8 (t), 127.9 (t), 128.0 (t), 128.1 (t), 128.3 (t), 128.4 (t),
137.6 (q).
HRMS (ESI): m/z calcd for C27H35N4O5 [M + NH4]+: 495.2602;
found: 495.2604.
Yield: 78 mg (95%); [a]D16 –4 (c 1.0, CHCl3).
IR (KBr): 3360, 2928, 2856, 1455, 1092, 837, 735, 696 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.03 (s, 6 H, 2 × SiCH3), 0.88 (s,
9 H, t-Bu), 1.99 (s, 1 H, NH), 3.39 (dd, J = 12.0, 6.0 Hz, 1 H, H-5),
3.59 (dd, J = 11.6, 5.6 Hz, 1 H, H-2), 3.68 (t, J = 7.6 Hz, 1 H, H-
5¢a), 3.72–3.77 (m, 2 H, H-2¢a, 5¢b), 3.84 (dd, J = 12.0, 6.4 Hz, 1 H,
H-2¢b), 4.07–4.09 (m, 2 H, H-3, 4), 4.51 (s, 2 H, CH2Ph), 4.55 (d,
J = 12.0 Hz, 1 H, CH2Ph), 4.62 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.67
(d, J = 12.0 Hz, 1 H, CH2Ph), 4.72 (d, J = 12.0 Hz, 1 H, CH2Ph),
7.25–7.32 (m, 15 H, ArH).
13C NMR (100 MHz, CDCl3): d = –5.3 (p, SiCH3), 18.2 (q), 25.9
(p), 57.3 (t, C-2), 59.8 (t, C-5), 62.9 (s, C-2¢), 70.6 (s, C-5¢), 72.9 (s),
73.0 (s), 73.1 (s), 79.1 (t, C-3), 79.7 (t, C-4), 127.3 (t), 127.4 (t),
127.5 (t), 127.7 (t), 128.2 (t), 128.3 (t), 138.2 (q), 138.4 (q), 138.6
(q).
1-O-(tert-Butyldimethylsilyl)-2-deoxy-2-azido-3,4,6-tri-O-ben-
zyl-D-altritol (11)
To a stirred soln of 10 (1.90 g, 4.0 mmol) in anhyd py (20 mL) were
added TBSCl (650 mg, 4.3 mmol) and DMAP (20 mg, 0.16 mmol)
at 0 °C under argon. The mixture was stirred overnight at r.t., and
the solvent was removed in vacuo. Flash chromatography of the res-
idue (silica gel, PE–EtOAc, 5:1) gave 11 as a colorless oil.
Yield: 2.24 g (95%); [a]D16 +15 (c 1.0, CHCl3).
IR (KBr): 3436, 2929, 2099 (s, N3), 1456, 1106, 736, 698 cm–1.
HRMS (ESI): m/z calcd for C33H46NO4Si [M + H]+: 548.3191;
1H NMR (300 MHz, CDCl3): d = 0.06 (s, 3 H, SiCH3), 0.07 (s, 3 H,
SiCH3), 0.89 (s, 9 H, t-Bu), 2.59 (br, 1 H, OH), 3.56–3.85 (m, 6 H),
3.93 (t, J = 3.9 Hz, 1 H), 4.09 (td, J = 6.6, 3.9 Hz, 1 H), 4.48 (d,
J = 12.0 Hz, 1 H), 4.52 (d, J = 12.0 Hz, 1 H), 4.62 (d, J = 11.1 Hz,
1 H), 4.66 (d, J = 11.1 Hz, 1 H), 4.69 (d, J = 11.1 Hz, 1 H), 4.71 (d,
J = 11.1 Hz, 1 H), 7.23–7.35 (m, 15 H, ArH).
13C NMR (75 MHz, CDCl3): d = –5.5 (p, SiCH3), 18.2 (q), 25.8 (p),
63.3 (s, C-1), 63.8 (t, C-2), 70.6 (t, C-5), 71.1 (s, C-6), 73.3 (s), 73.6
(s), 74.1 (s), 78.2 (t, C-3), 79.3 (t, C-4), 127.7 (t), 127.8 (t), 127.9
(t), 128.0 (t), 128.4 (t), 137.7 (q), 137.8 (q), 137.9 (q).
found: 548.3197.
1-O-(tert-Butyldimethylsilyl)-2-deoxy-2-azido-3,4,6-tri-O-ben-
zyl-5-oxo-D-altritol (12)
To a soln of 11 (150 mg, 0.25 mmol) in anhyd CH2Cl2 (3 mL) was
added DMP (120 mg, 0.28 mmol) at r.t. The mixture was stirred
overnight, and then concentrated in vacuo. Flash chromatography
of the residue (silica gel, PE–EtOAc, 5:1) gave 12 as a colorless oil.
Yield: 134 mg (91%); [a]D16 –3 (c 1.0, CHCl3).
IR (KBr): 3370, 2926, 2100 (s, N3), 1732, 1105, 837, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.05 (s, 3 H, SiCH3), 0.06 (s, 3 H,
SiCH3), 0.89 (s, 9 H, t-Bu), 3.61–3.66 (m, 1 H), 3.65 (dd, J = 10.5,
4.8 Hz, 1 H), 3.80 (dd, J = 10.5, 6.6 Hz, 1 H), 3.98 (t, J = 4.8 Hz, 1
H), 4.19 (d, J = 18.9 Hz, 1 H), 4.23 (d, J = 6.6 Hz, 1 H), 4.30 (d,
J = 18.9 Hz, 1 H), 4.43 (d, J = 11.7 Hz, 1 H), 4.49 (d, J = 11.7 Hz,
1 H), 4.53 (s, 4 H), 7.24–7.34 (m, 15 H, ArH).
13C NMR (75 MHz, CDCl3): d = –5.6 (p, SiCH3), 18.1 (q), 25.7 (p),
62.9 (s, C-1), 63.6 (t, C-2), 72.8 (s), 73.2 (s), 74.5 (s), 74.8 (s), 78.8
(t, C-3), 80.6 (t, C-4), 127.9 (t), 128.0 (t), 128.2 (t), 128.3 (t), 128.4
(t), 128.5 (t), 136.6 (q), 137.0 (q), 137.1 (q), 207.5 (q, C=O).
HRMS (ESI): m/z calcd for C33H45N3O5SiNa [M + Na]+: 614.3021;
found: 614.3027.
1-O-(tert-Butyldimethylsilyl)-2-deoxy-2-azido-5-O-methane-
sulfonyl-3,4,6-tri-O-benzyl-D-altritol (3)
To a soln of 11 (130 mg, 0.22 mmol) in anhyd py (2 mL) was added
MsCl (0.1 mL, 1.28 mmol). The mixture was stirred for 3 h at r.t.,
quenched with brine (3 mL), and extracted with CH2Cl2 (3 × 5 mL).
The organic extracts were washed with brine (5 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. Flash chromatogra-
phy of the residue (silica gel, PE–EtOAc, 5:1) gave 3 as a colorless
oil.
HRMS (ESI): m/z calcd for C33H47N4O5Si [M + NH4]+: 607.3310;
Yield: 143 mg (97%); [a]D16 –4 (c 1.0, CHCl3).
found: 607.3315.
IR (KBr): 3358, 2930, 2101 (s, N3), 1358, 1105, 838, 740 cm–1.
(2R,3S,4R,5R)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-5-
[(tert-butyldimethylsiloxy)methyl]pyrrolidine (2)
1H NMR (300 MHz, CDCl3): d = 0.05 (s, 3 H, SiCH3), 0.06 (s, 3 H,
SiCH3), 0.89 (s, 9 H, t-Bu), 3.00 (s, 3 H, CH3SO3), 3.62 (td, J = 7.2,
3.0 Hz, 1 H), 3.71–3.85 (m, 5 H), 3.97 (dd, J = 6.6, 1.8 Hz, 1 H),
4.45 (s, 2 H, CH2Ph), 4.58 (d, J = 11.4 Hz, 1 H, CH2Ph), 4.61 (s, 2
H, CH2Ph), 4.77 (d, J = 11.4 Hz, 1 H, CH2Ph), 5.14–5.17 (m, 1 H),
7.25–7.38 (m, 15 H, ArH).
13C NMR (75 MHz, CDCl3): d = –5.6 (p, SiCH3), 18.1 (q), 25.7 (p),
38.4 (p), 62.7 (s, C-1), 63.0 (t, C-2), 68.9 (s, C-6), 73.2 (s), 73.6 (s),
74.5 (s), 77.1 (t, C-3), 79.1 (t, C-4), 82.4 (t, C-5), 127.7 (t), 127.8 (t),
127.9 (t), 128.0 (t), 128.2 (t), 128.4 (t), 137.1 (q), 137.2 (q), 137.3
(q).
To a stirred soln of 12 (120 mg, 0.20 mmol) in anhyd MeOH (3 mL)
was added one portion of NaBH4 (19 mg, 0.20 mmol) at 0 °C under
argon. The mixture was stirred at 0 °C for 2 h, and quenched by ad-
dition of glacial AcOH (0.1 mL). The solvent was removed in vac-
uo. Flash chromatography of the residue (silica gel, PE–EtOAc,
2:1) gave a mixture of 4 and 11 as a colorless oil (118 mg, 99%).
The mixture was treated according to the description above for the
preparation of 3 and 1, and compounds 2 and 1 were separated by
flash chromatography (silica gel, PE–EtOAc, 3:1). The NMR data
of 1 was identical to that described above, and the data for 2 are giv-
en below.
HRMS (ESI): m/z calcd for C34H51N4O7SSi [M + NH4]+: 687.3242;
found: 687.3236.
Yield (1): 24 mg (22%); yellowish oil.
Yield (2): 76 mg (69%); yellowish oil; [a]D16 +41 (c 1.0, CHCl3).
IR (KBr): 3357, 2927, 2855, 1455, 1090, 837, 735, 697 cm–1.
Synthesis 2007, No. 9, 1359–1365 © Thieme Stuttgart · New York

1364
L. Zhou et al.
PAPER
IR (KBr): 2926, 1734, 1700, 1388, 1162, 1107, 737, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.40 (s, 9 H, t-Bu), 3.80–4.00 (m,
2 H), 4.13–4.27 (m, 4 H), 4.42–4.56 (m, 2 H), 4.67–4.76 (m, 4 H),
7.24–7.35 (m, 15 H, ArH), 9.43 (s, 1 H, CHO).
13C NMR (100 MHz, CDCl3): d = 28.2 (p), 58.5 (t), 66.1 (t), 68.1
(s), 73.1 (s), 73.2 (s), 73.5 (s), 77.9 (t), 81.1 (t, q, overlapping),
127.5 (t), 127.6 (t), 127.8 (t), 128.27 (t), 128.34 (t), 137.5 (q), 138.0
(q), 138.4 (q), 154.4 (q, C=O), 200.6 (t, CHO).
1H NMR (400 MHz, CDCl3): d = 0.05 (s, 6 H, 2 × SiCH3), 0.89 (s,
9 H, t-Bu), 1.98 (s, 1 H, NH), 3.45 (td, J = 7.2, 4.0 Hz, 1 H, H-2),
3.52–3.63 (m, 3 H, H-2¢a, 5, 5¢a), 3.81 (dd, J = 10.0, 7.2 Hz, 1 H, H-
2¢b), 3.86 (dd, J = 10.4, 8.0 Hz, 1 H, H-5¢b), 3.92 (dd, J = 7.2, 4.0
Hz, 1 H, H-4), 4.11 (t, J = 4.0 Hz, 1 H, H-3), 4.40 (d, J = 12.0 Hz, 1
H, CH2Ph), 4.44 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.52 (d, J = 11.2 Hz,
1 H, CH2Ph), 4.54 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.65 (d, J = 11.6
Hz, 1 H, CH2Ph), 4.74 (d, J = 11.6 Hz, 1 H, CH2Ph), 7.24–7.37 (m,
15 H, ArH).
13C NMR (100 MHz, CDCl3): d = –5.4 (p, SiCH3), 18.2 (q), 25.9 (t),
59.7 (t, C-2), 60.9 (s, C-2¢), 61.1 (t, C-5), 69.6 (s, C-5¢), 72.3 (s),
73.2 (s), 73.3 (s), 76.7 (t, C-3), 80.0 (t, C-4), 127.5 (t), 127.6 (t),
127.7 (t), 128.2 (t), 128.3 (t), 137.9 (q), 138.0 (q), 138.4 (q).
HRMS (ESI): m/z calcd for C32H38NO6 [M + H]+: 532.2694; found:
532.2685.
(E)-[(2¢R,3¢S,4¢R,5¢S)-N-(tert-Butyloxycarbonyl)-3¢,4¢-O-diben-
zyl-5¢-(O-benzylmethyl)pyrrolidin-2¢-yl]but-3-en-2-one (15)
To a stirred soln of 14 (750 mg, 1.41 mmol) in toluene (15 mL) was
added Ph3P=CHCOMe (1.10 g, 3.46 mmol), and the mixture was
refluxed for 24 h. The solvent was removed in vacuo. Flash chroma-
tography of the residue (silica gel, PE–EtOAc, 3:1) gave 15 as yel-
lowish oil.
HRMS (ESI): m/z calcd for C33H46NO4Si [M + H]+: 548.3191;
found: 548.3197.
(2R,3S,4R,5S)-N-(tert-Butyloxycarbonyl)-2-(hydroxymethyl)-
3,4-O-dibenzyl-5-(O-benzylmethyl)pyrrolidine (13)
To a soln of 1 (1.30 g, 2.37 mmol) in CH2Cl2 (15 mL) in the pres-
ence of Et3N (0.5 mL) was added Boc2O (725 mg, 3.32 mmol) un-
der argon. The mixture was stirred at r.t. overnight. The solvent was
removed in vacuo. Flash chromatography of the residue (silica gel,
PE–EtOAc, 5:1) gave the Boc-protected product as a yellowish oil.
Yield: 1.50 g (98%); [a]D22 –10 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.03 (s, 3 H, SiCH3), 0.04 (s, 3 H,
SiCH3), 0.87 (s, 9 H, t-BuSi), 1.46 (s, 9 H, t-BuO), 3.60–4.80 (m, 14
H), 7.25–7.33 (m, 15 H, ArH).
Yield: 572 mg (71%); [a]D22 +25 (c 1.0, CHCl3).
IR (KBr): 2925, 1696, 1671, 1367, 1164, 1104, 739, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.39 (s, 9 H, t-Bu), 2.12 (s, 3 H,
CH3), 3.84 (dd, J = 7.8, 5.7 Hz, 1 H), 4.02–4.10 (m, 3 H), 4.23 (t,
J = 4.2 Hz, 1 H), 4.40–4.60 (m, 4 H), 4.64 (d, J = 11.7 Hz, 1 H),
4.67 (d, J = 11.1 Hz, 1 H), 4.78 (d, J = 11.1 Hz, 1 H), 6.06 (br s, 1
H), 6.95 (dd, J = 16.5, 7.2 Hz, 1 H), 7.24–7.36 (m, 15 H, ArH).
13C NMR (75 MHz, CDCl3): d = 26.0 (p), 28.1 (p), 58.9 (t), 60.5 (t),
67.5 (s), 72.1 (s), 73.0 (s), 73.6 (s), 77.4 (t), 79.8 (t), 80.3 (q), 127.1
(t), 127.2 (t), 127.4 (t), 127.7 (t), 128.0 (t),128.2 (t), 131.7 (t), 137.4
(q), 138.1 (q), 138.4 (q), 145.9 (t), 154.7 (q, C=O), 198.7 (q, C=O).
13C NMR (100 MHz, CDCl3): d = –5.3 (p, SiCH3), 18.2 (q), 25.9
(p), 28.4 (p), 58.5 (t), 60.9 (t), 69.7 (s), 72.9 (s), 73.0 (s), 73.5 (s),
78.6 (t), 79.9 (q), 127.2 (t), 127.3 (t), 127.4 (t), 127.6 (t), 128.12 (t),
128.15 (t), 128.2 (t), 138.6 (q), 138.8 (q), 138.9 (q), 155.6 (q, C=O).
HRMS (ESI): m/z calcd for C35H42NO6 [M + H]+: 572.3007; found:
572.3004.
To a soln of the product produced above (1.50 g, 2.32 mmol) in an-
hyd THF (15 mL) was added TBAF·3H2O (1.46 g, 4.63 mmol). The
mixture was stirred at r.t. for 24 h. The solvent was removed in vac-
uo, and flash chromatography of the residue (silica gel, PE–EtOAc,
3:1) gave 13 as yellowish oil.
Yield: 1.20 g (97%); [a]D22 –10 (c 1.0, CHCl3).
IR (KBr): 2929, 2875, 1692, 1392, 1164, 1111, 738, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.42 (s, 9 H, t-Bu), 3.68–3.98 (m,
4 H), 4.06–4.17 (m, 4 H), 4.42–4.58 (m, 3 H), 4.51–4.75 (m, 3 H),
7.25–7.33 (m, 15 H, ArH).
13C NMR (100 MHz, CDCl3): d = 28.3 (p), 58.9 (t), 60.1 (t), 61.3 (t),
62.8 (s), 68.5 (s), 72.8 (s), 73.2 (s), 74.0 (s), 78.5 (t), 80.6 (q), 127.45
(t), 127.51 (t), 127.6 (t), 127.8 (t), 128.25 (t), 128.30 (t), 128.4 (t),
137.6 (q), 138.0 (q), 138.3 (q), 156.3 (q, C=O).
Intermediate Ketone 16
Compound 15 (150 mg, 0.26 mmol) in MeOH (15 mL) was hydro-
genated at 1 bar over Pd/C (10%, 40 mg) for 12 h. An aliquot was
concentrated, and flash chromatography of the residue (silica gel,
PE–EtOAc, 2:1) gave 16 as yellowish oil.
[a]D22 +9 (c 1.0, CHCl3).
IR (KBr): 2927, 1692, 1366, 1168, 1105, 738, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.41 (s, 9 H, t-Bu), 1.97–2.15 (m,
2 H), 2.07 (s, 3 H, CH3), 2.44 (t, J = 6.3 Hz, 2 H), 3.77–3.99 (m, 5
H), 4.17 (t, J = 4.8 Hz, 1 H), 4.51 (br s, 2 H), 4.62 (d, J = 12.3 Hz,
1 H), 4.68 (d, J = 12.3 Hz, 1 H), 4.70 (d, J = 11.1 Hz, 1 H), 4.82 (d,
J = 11.1 Hz, 1 H), 7.22–7.36 (m, 15 H, ArH).
13C NMR (75 MHz, CDCl3): d = 24.1 (s), 28.2 (p), 29.7 (p), 40.4 (s),
57.6 (t), 58.8 (t), 68.3 (s), 72.2 (s), 73.0 (s), 73.8 (s), 78.7 (t), 79.9
(q), 127.2 (t), 127.3 (t), 127.5 (t), 128.0 (t), 128.1 (t), 128.2 (t), 138.0
(q), 138.3 (q), 138.7 (q), 155.5 (q, C=O), 208.7 (q, C=O).
HRMS (ESI): m/z calcd for C32H40NO6 [M + H]+: 534.2850; found:
534.2847.
[(2¢S,3¢S,4¢R,5¢S)-N-(tert-Butyloxycarbonyl)-3¢,4¢-O-dibenzyl-
5¢-(O-benzylmethyl)pyrrolidin-2¢-yl]carbaldehyde (14)
To a stirred soln of (COCl)2 (0.29 mL, 3.38 mmol) in CH2Cl2 (6
mL) was added a soln of DMSO (0.53 mL, 7.46 mmol) at –78 °C in
CH2Cl2 (3 mL). After the mixture had stirred for 10 min, a soln of
13 (1.2 g, 2.25 mmol) in CH2Cl2 (5 mL) was added and the stirring
was continued at this temperature for 20 min. Then Et3N (2.3 mL,
16.4 mmol) was added, and the mixture was allowed to warm to r.t.
over 1 h, and quenched with a sat. NH4Cl soln (15 mL). The mixture
was extracted with CH2Cl2 (3 × 20 mL), and the organic extracts
were dried (Na2SO4), filtered, and concentrated in vacuo. Flash
chromatography of the residue (silica gel, PE–EtOAc, 5:1) gave 14
as yellowish oil.
HRMS (ESI): m/z calcd for C35H44NO6 [M + H]+: 574.3163; found:
574.3153.
5-epi-Hyacinthacine A4 [(1S,2R,3S,5R,7aR)-1,2-dihydroxy-3-
(hydroxymethyl)-5-methylpyrrolizidine; 18]
Concentrated HCl (2 mL) was added to the mixture with 16 ob-
tained above and the combined mixture was further stirred for 30 h.
The catalyst was collected by filtration and washed with MeOH (3
× 2 mL), and the filtrate and washings were neutralized with Am-
berlite IRA-400 (OH– form) and then hydrogenated again with 10%
Pd/C (40 mg) at 4 bar for 3 d. The catalyst was removed, and the
filtrate and washings were concentrated in vacuo. Flash chromatog-
raphy of the residue (silica gel, Et2O–MeOH–Et3N, 5:1:0.1) gave 18
as yellowish oil.
Yield: 1.13 g (94%); [a]D22 +1 (c 1.0, CHCl3).
Synthesis 2007, No. 9, 1359–1365 © Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Pyrrolidines and 5-epi-Hyacinthacine A4
1365
Yield: 20 mg (41%, from 15); [a]D22 –10 (c 1.0, MeOH).
IR (KBr): 3418, 2962, 1644, 1227 cm–1.
(7) (a) Ikota, N. Tetrahedron Lett. 1992, 33, 2553. (b) Ikota,
N.; Nakagawa, H.; Ohno, S.; Noguchi, K.; Okuyama, K.
Tetrahedron 1998, 54, 8985. (c) Subramanian, T.; Lin, C.-
C.; Lin, C.-C. Tetrahedron Lett. 2001, 42, 4079.
(8) Furneaux, R. H.; Gainsford, G. J.; Manson, J. M.; Tyler, P.
C. Tetrahedron 1991, 50, 2131.
1H NMR (300 MHz, CDCl3): d = 1.17 (d, J = 6.6 Hz, 3 H, Me),
1.49–1.80 (m, 3 H), 2.07–2.20 (m, 1 H), 2.64–2.72 (m, 2 H, H-3, 5),
3.31–3.38 (m, 1 H, H-7a), 3.67 (dd, J = 11.1, 4.5 Hz, 1 H, H-8), 3.78
(dd, J = 11.1, 1.8 Hz, 1 H, H-8¢), 3.87 (dd, J = 4.5, 2.7 Hz, 1 H, H-
2), 4.44 (dd, J = 8.4, 4.5 Hz, 1 H, H-1).
13C NMR (75 MHz, CDCl3): d = 19.6 (s, C-7), 20.6 (p, C-9), 35.5
(s, C-6), 55.8 (t, C-5), 60.1 (s, C-8), 61.8 (t, C-3), 67.7 (t, C-7a), 70.1
(t, C-1), 78.4 (t, C-2).
(9) (a) Denmark, S. E.; Herbert, B. J. Am. Chem. Soc. 1998, 120,
7357. (b) Denmark, S. E.; Martinborough, E. A. J. Am.
Chem. Soc. 1999, 121, 3046. (c) Denmark, S. E.; Hurd, A.
R. Org. Lett. 1999, 1, 1311. (d) Denmark, S. E.; Hurd, A. R.
J. Org. Chem. 2000, 65, 2875. (e) Denmark, S. E.; Herbert,
B. J. Org. Chem. 2000, 65, 2887. (f) Denmark, S. E.;
Cottell, J. J. J. Org. Chem. 2001, 66, 4276. (g) Toyao, A.;
Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003, 35.
(h) Cardona, F.; Faggi, E.; Liguori, F.; Cacciarini, M.; Goti,
A. Tetrahedron Lett. 2003, 44, 2315. (i) Gallos, J. K.; Sarli,
V. C.; Stathakis, C. I.; Koftis, T. V.; Nachmia, V. R.;
Coutouli-Argyropoulou, E. Tetrahedron 2002, 58, 9351.
(10) Romero, A.; Wong, C.-H. J. Org. Chem. 2000, 65, 8264.
(11) (a) Rambaud, L.; Compain, P.; Martin, O. R. Tetrahedron:
Asymmetry 2001, 12, 1807. (b) White, J. D.; Hrnciar, P. J.
Org. Chem. 2000, 65, 9129. (c) Tang, M.; Pyne, S. G. J.
Org. Chem. 2003, 68, 7818. (d) Dewi-Wülfing, P.;
Blechert, S. Eur. J. Org. Chem. 2006, 1852.
HRMS (ESI): m/z calcd for C9H18NO3 [M + H]+: 188.1281; found:
188.1284.
Acknowledgment
Projects 20472025 and 20621091 are supported by the National Na-
tural Science Foundation of China. We gratefully acknowledge Pro-
fessor Xin-Shan, Ye, Perking University, for his valuable advice
and suggestions.
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Synthesis 2007, No. 9, 1359–1365 © Thieme Stuttgart · New York