A flexible enantioselective approach to 3,4-dihydroxyprolinol derivatives by SmI2-mediated reductive coupling of chiral nitrone with ketones/aldehydes

Article abstract of DOI:10.1016/j.tet.2012.06.006

A flexible enantioselective approach to polyhydroxylated prolinol derivatives was described, which is based on the samarium diiodide-mediated reductive coupling of the chiral nitrone (3S,4R)-8, derived from d-isoascorbic acid with aldehydes/ketones. Thereby, polyhydroxyprolinol derivatives 9a-e and 9h-j were obtained from aromatic ketones and aliphatic aldehydes in good to excellent yields of 65-91%. These reductive hydroxyalkylations are highly diastereoselective in establishing the C-4 stereogenic center. By this way, the asymmetric syntheses of (-)-8a-epi-swainsonine (4) and (-)-8,8a-di-epi- swainsonine (5) have been achieved.

Full text of DOI:10.1016/j.tet.2012.06.006

Tetrahedron 68 (2012) 6656e6664
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A flexible enantioselective approach to 3,4-dihydroxyprolinol derivatives
by SmI2-mediated reductive coupling of chiral nitrone with ketones/aldehydes
*
Hong-Kui Zhang , Shou-Qiang Xu, Jia-Jia Zhuang, Jian-Liang Ye, Pei-Qiang Huang
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, PR
China
a r t i c l e i n f o
a b s t r a c t
Article history:
A flexible enantioselective approach to polyhydroxylated prolinol derivatives was described, which is
based on the samarium diiodide-mediated reductive coupling of the chiral nitrone (3S,4R)-8, derived
from D-isoascorbic acid with aldehydes/ketones. Thereby, polyhydroxyprolinol derivatives 9aee and
9hej were obtained from aromatic ketones and aliphatic aldehydes in good to excellent yields of
65e91%. These reductive hydroxyalkylations are highly diastereoselective in establishing the C-4 ster-
eogenic center. By this way, the asymmetric syntheses of (ꢀ)-8a-epi-swainsonine (4) and (ꢀ)-8,8a-di-epi-
swainsonine (5) have been achieved.
Received 25 February 2012
Received in revised form 23 May 2012
Accepted 1 June 2012
Available online 13 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
used as versatile organocatalysts for a number of enantioselective
reactions.13 All of these compounds share with the common
Polyhydroxylated pyrrolidine/piperidine-containing alkaloids
are known as aza-sugars or iminosugars, because these compounds
can be regarded as monosaccharide analogs with nitrogen replac-
ing the ring oxygen. Accordingly, they are considered as the mimics
of sugars. Indeed, many aza-sugars and their stereoisomers exhibit
potent inhibitory activity toward carbohydrate-processing en-
zymes,1 which make them promising both for the treatment of
metabolite disorder-associated diseases, and as invaluable molec-
ular tools for study of the mechanism of action of carbohydrate-
structure of compound A. Consequently, the enantioselective syn-
thesis of polyhydroxylated pyrrolidine/piperidine-containing al-
kaloids and their stereoisomers has attracted considerable
attention, which cumulated in
a
number of synthetic
approaches.14,15
HO
OH
HO
OH
OH
OH
processing enzymes.2 For example, 1,4-dideoxy-1,4-imino-
itol (DIL, 1) is a potent competitive inhibitor of
-galactosidase,3
while its diastereomer 1,4-dideoxy-1,4-imino- -ribitol (DRB, 2)
strongly inhibited the activities of eukaryotic DNA polymerases
with IC50 values of 21e35
M (Fig. 1).4 Indolizidine alkaloid
D-lyx-
N
H
. DIL
N
H
. DRB
a
1
2
D
1,4-dideoxy-1,4-imino-
D
-lyxitol 1,4-dideoxy-1,4-imino-D-ribitol
m
(ꢀ)-swainsonine (3), first isolated from the fungus Rhizoctonia
OH
OH
OH
HO
HO
H
HO
Leguminicola in 19735 and later found in several plants and fungi,6
H
H
is found to be a potent
a-mannosidase and mannosidase II in-
HO
HO
HO
hibitor.7 (ꢀ)-Swainsonine (3) is also a potential drug for treating
cancer, HIV, and immunological disorders.8 As a stereoisomer of
swainsonine, 8a-epi-swainsonine9 (4) exhibited glucosidase in-
hibitory activities.10 8,8a-Di-epi-swainsonine9e,f,11 (5), another ste-
reoisomer of swainsonine, is a powerful competitive inhibitor of
N
N
N
3.
swainsonine
4. 8a-epi-
5. 8,8a-di-epi-
swainsonine
swainsonine
HO
OH
HO
OH
human acidic (lysosomal) a-D
-mannosidase.11b Compound 6, pos-
Ph
HO
*
*
sessing partial structure of swainsonine, is a very potent inhibitor of
Me
H
Ph
N
H
N
H
R2
R1
-mannosidases.12 In addition, prolinol derivatives 7a/7b have been
OP
N
H
D
OH
1
7a
. P = H
A
(R = Alkyl, aryl;
7b
. P = TMS
6
R2 = H, Alkyl, aryl)
* Corresponding author. E-mail address: hkzhang@xmu.edu.cn (H.-K. Zhang).
Fig. 1. Some prolinol-based bioactive molecules and catalysts.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.006

H.-K. Zhang et al. / Tetrahedron 68 (2012) 6656e6664
6657
Nitrones are a class of versatile synthetic intermediates, which
exhibit a broad spectrum of reactivity and have widespread appli-
cations in organic synthesis including [2þ3] cycloaddition16 and
nucleophilic addition with various organometallic reagents.17 Re-
cently, synthetic applications of nitrones have been extended to the
reaction. Indeed, addition of nitrone 8 to a mixture of cyclohexa-
none and SmI2 afforded 9f in 42% yield, and reduced product 11 in
21% yield (Table 1, entry 9). However, treatment of nitrone 8 with
acetone produced only the reduced product 11 in 70% yield, with
neither the desired reductive coupling product nor pinacolic
product being obtained (Table 1, entry 10).
SmI2-mediated coupling reactions with
a,b-unsaturated amides/
esters18 and carbonyl compounds.19
We next examined SmI2-mediated reductive coupling of
(3S,4R)-8 with aliphatic aldehydes. Under the conditions estab-
lished for the coupling reaction with ketones (nitrone/ketone/SmI2/
H2O¼1.0:1.5:3.0:10.0, equiv), the coupling of nitrone 8 with n-bu-
tyraldehyde gave a low yield of 9h (50%). An improved yield (72%)
was obtained with 2.0 equiv of n-butyraldehyde and 2.0 equiv of
SmI2 (Table 1, entry 11). Under the same conditions, the reaction
with iso-butyraldehyde gave an 80% yield, while that with sterically
more hindered pivalaldehyde gave a lower yield (65%) accompa-
nying with a 20% of the reduced product (Table 1, entries 12 and 13).
As regarding the diastereoselectivity of the cross-coupling re-
actions, the reaction of the asymmetric aromatic ketones led to two
diastereomers, while the coupling with aliphatic aldehydes pro-
duced three diastereomers. The stereochemistries of the coupling
products 9aH and 9aL were tentatively determined by NOESY ex-
periments. As showed in Fig. 2, no correlation was observed be-
tween H-4 and H-6a for diastereomers 9aH and 9aL, which
suggested a trans-relationship between the two protons in both
diastereomers. Determination of the stereochemistry of the exo-
As a continuation of our interest in the enantioselective syn-
thesis of hydroxylated prolinols via SmI2-mediated cross coupling
of enantiopure pyrrolidine-based nitrones with carbonyl com-
pounds,19bed we now report the SmI2-mediated reductive cross
coupling of -isoascorbic acid derived nitrone (3S,4R)-8 with car-
D
bonyl compounds, and its application to the asymmetric synthesis
of (ꢀ)-8a-epi-swainsonine (4) and (ꢀ)-8,8a-di-epi-swainsonine (5).
2. Results and discussion
The enantiomerically pure nitrone (3S,4R)-8 is easily prepared
from D
-isoascorbic acid by the known method.20 In view of the
recent results from the groups of Py,19eeg,21 Skrydstrup,22 and our
laboratory,19a,ced SmI2eH2O combination was selected as the re-
agent system for our study. First, the reductive coupling reaction of
nitrone (3S,4R)-8 with acetophenone was investigated (Scheme 1).
Thus, to a THF solution of (3S,4R)-8 (1.0 equiv) and acetophe-
none (1.5 equiv) were treated with degassed water (10.0 equiv)21f,23
O
O
O
O
O
O
SmI2 (3.0 eq.)
H2O (10 eq.)
Ph
Me
Ph
Me
O
H
H
C6H5
Me
Me
C6H5
+
+
+
N
N
C6H5
Me
HO
OH
N
O
THF, −78 °C
OH
OH
OH
OH
2 h
10
9aH
9aL
8
Scheme 1. Reductive coupling reaction of (3S,4R)-8 with acetophenone.
and a freshly prepared 0.1 M THF solution of samarium diiodide19a
(3.0 equiv) at ꢀ78 ꢁC for 2 h, the desired cross coupling product 9a
was obtained as a separable mixture of two diastereomers in a ratio
of 9aH/9aL¼1:1.5 (combined yield: 91%), along with 10% of the
pinacolic coupling side product 10 (Table 1, entry 3). No reduced
product was observed. Using less SmI2 (2.0 equiv) led to lower yield
(70%), and 10% of pinacolic coupling side product, along with 20% of
the recovered starting nitrone. When 1.0 equiv of acetophenone
and 3.0 equiv of SmI2 were used, the desired coupling product (68%
yield) and some pinacolic product, in addition to the recovered
starting nitrone (20%) were isolated (entry 2). This result indicated
the importance of using an excess of ketone. Thus, in the sub-
sequent investigations, at least 1.5 equiv of ketone was used. Finally,
comparing the conditions showed in entries 3 and 4 allowed us to
define the optimal reaction conditions, namely, with a ratio of
nitrone/ketone/SmI2/H2O¼1.0:1.5:3.0:10.0 (equiv). Under the op-
timal conditions, similar results were obtained with other aromatic
ketones even with sterically hindered benzophenone (Table 1, en-
tries 5e8). However, the reaction with 2.0 equiv of cyclohexanone
and 2.0 equiv of SmI2 yielded the desired coupling product 9f in
only 16% yield, along with 52% of the reduced product 11 (Table 1,
entry 9), while no pinacolic product 10 was observed. The low yield
of the coupling product, and no pinacolic product being formed can
be understood by the remarkable difference between aliphatic
ketones and aromatic ketones in the capacity of obtaining an
electron from SmI2 to form a ketyl intermediate. It was envisioned
that use of inversed addition protocol would improve the coupling
cyclic carbinolic carbon by NOESY experiment is less evident. The
proton assignment was made jointly by 1He1H COSY, HSQC and
HMBC experiments. A NOE correlation between the a-phenyl pro-
ton and H-3a was observed for the major diastereomer 9aL, but not
for the minor diastereomer 9aH, allowing a tentative assignment of
the C-7 stereochemistry of diastereomer 9aL as R and that of 9aH as
S. On the other hand, feature 1H NMR spectra for all diastereomers
obtained from the aromatic ketones show the similar characters:
the H-4 protons resonance at higher field (3.49e3.52 ppm) and
exhibit larger coupling constants (J3a,4¼4.8e5.1 Hz) for products
9aHedH, whereas those of 9aLecL resonance at lower field
(3.63e3.67 ppm) and gave smaller coupling constants
(J3a,4¼2.6e2.9 Hz) (Table 2). On the basis of the consideration of
above mentioned information, H-3a/H-4 trans stereochemistry was
assigned for all diastereomers 9bHedH and 9bLedL, respectively. It
is reasonable to assume that the stereochemistry outcome of the
cross-coupling reaction is a result of the approach of the ketyl
radical from the less hindered side opposing the acetonide cycle.
Thus, the 3a,4-stereochemistries of the coupling products with al-
dehydes were also deduced to be trans. This was confirmed by the
synthesis of the known compound 12/13 and 4/5 (vide infra),
respectively.
To demonstrate the utility of the method, the syntheses of 8a-
epi-swainsonine (4) and 8,8a-di-epi-swainsonine (5), stereoisomers
of swainsonine (3) were undertaken. A simple retrosynthetic
analysis suggested indolizidinone derivatives 12/13 as precursors of
the target molecules 4/5. Compounds 12/13 were envisioned to be

Table 1
The reductive coupling reactions of (3S,4R)-8 with aldehydes/ketones
O
O
O
O
O
O
R2
R1
O
O
R2
R1
O
H
H
R2
R1
SmI2
R1
R2
+
+
+
+
HO
OH
R2
R1 = Aryl, alkyl
H2O, THF
–78 °C, 2 h
N
R1
N
N
N
O
OH
OH
OH
OH
OH
11
10
R2 = H, aryl, alkyl
9H
9L
8
Entry
Aldehyde/ketone (equiv)
SmI2 (equiv)
H2O (equiv)
Product
Yield (%)
Pinacolic
Reduced
Ratiod 9H/9L
product 10 (%)
product 11 (%)
O
1
2
3
4
1.5
1.0
1.5
1.5
2.0
3.0
3.0
3.0
10
10
10
15
9a
9a
9a
9a
70a
68a
91
10c
0
39:61
41:59
40:60
40:60
10c
10c
10c
0
0
0
90
O
5
6
7
1.5
1.5
1.5
3.0
3.0
3.0
10
10
10
9b
9c
9d
89
87
90
85
10c
10a
10c
0
0
0
0
48:52
52:48
54:46
MeO
O
MeO
O
Me2N
O
8
9
1.5
2.0
3.0
2.0
10
10
9e
9f
10c
0
/
/
O
O
16
52
(42b)
(21b)
10
11
2.0
2.0
2.0
2.0
10
10
9g
9h
0
0
0
70
0
/
Me
Me
O
72
51:32
n
C3H7
H
H
O
12
13
2.0
2.0
2.0
2.0
10
10
9i
9j
80
65
0
0
3
54:33
62:29
i
C3H7
O
20
H
But
a
Recovered 20% nitrone.
b
c
Addition of nitrone/THF solution to a mixture of ketone and SmI2.
Based on ketone.
d
Determined by 1H NMR.

H.-K. Zhang et al. / Tetrahedron 68 (2012) 6656e6664
6659
1.36
1.56
1.16
1.49
H3C
O
CH3
H3C
O
7.36
CH3
H
Me
O3
7.47
H
Me
1 O
O
2
7.H27
O
4. 47H
4.90
1. 54
CH3
4.66 H
H
1.68
H
4. 35
CH3
H
H
3.46
3. 46
7. 45
H
H
H
OH
6a
6
3a
4
H
Me
OH
2. 99
H
N
7.36
H
3.27H
N
H
H
7.35
3.68
H
3.52
H
7.47
7
N5
OH
OH
OH
H
H
Ph
OH
H
7.24
H
7.45
H
7.35
9a
9aL
9aH
Fig. 2. Observed NOE correlations (in part) for diastereomers 9aH and 9aL.
Table 2
H-4 Chemical shifts/coupling constants and C-7 stereochemistries of the diastereomers of 9aed
O
O
O
O
O
O
O
O
H
H
H
H
Compound
N
O
O
N
OH
N
OH
N
OH
N
OH
OH
OH
OH
OH
dH-4(ppm)/J3a,4 (Hz)
C-7 Chirality
dH-4(ppm)/J3a,4 (Hz)
C-7 Chirality
9aH
9aL
3.52/5.0
Sa
9bH
9bL
3.50/4.8
S
3.63/2.9
R
9cH
9cL
3.50/4.9
S
3.73/2.6
R
9dH
9dL
3.49/5.1
S
3.67/2.6
R
3.68/2.9
Ra
a
Determined by NOE technique.
accessible from the SmI2-mediated reductive coupling of methyl 4-
oxo-butanoate (14) with nitrone 8 (Scheme 2).
and the results are summarized in Table 3. First, nitrone 8 and al-
dehyde 14 (2.0 equiv) was treated with SmI2 (2.0 equiv) in the
presence of 10.0 equiv of degassed water at ꢀ78 ꢁC for 2 h to afford
the coupling product 15 (contained 15a, 15b, and 15c, combined
yield: 60%) (Table 3, entry 1). Using 3.0 equiv of SmI2, the yield of 15
was improved to 70% with 5% of reduced product isolated. Under
similar reaction conditions but using 15.0 equiv of water, the yield
was improved up to 80%, and no reduced product was observed
(Table 3, entry 3). The chemical yield was further improved to 89%
by running the reaction with 5.0 equiv of aldehyde (14) and
20.0 equiv of H2O (Table 3, entry 4). The 1H NMR spectrum analysis
showed that the coupling product 15 (obtained under the reaction
conditions in entry 4, Table 3) is a mixture containing three di-
astereomers in a ratio of 15a/15b/15c¼50:41:9, from which it is
difficult to isolate the pure diastereomers using column chroma-
tography on silica gel. However, without isolation, the mixed
product could be directly used for next cyclization. Furthermore,
the stereochemistries of the major products 15a/15b could be
O
O
HO
OH
O
O
O
1
2
H
H
8
OMe
8a
OH
OH
+
H
N
N
N
O
8
O
14
O
12 (1S,2R,8R,8aS)-
(1S,2R,8S,8aS)-
4
(1S,2R,8R,8aS)-
(1S,2R,8S,8aS)-
13
5
Scheme 2. Retrosynthetic analysis for the target molecules 4 and 5.
The requisite aldo-ester 14 was prepared from g-butyrolactone
by the Burgin’s procedure24 in an overall yield of 56%. Then, the
reductive coupling of (3S,4R)-8 with aldehyde 14 was investigated,
Table 3
The cross-coupling reaction of nitrone 8 with aldo-ester 14
O
O
O
O
O
O
O
O
H
OMe
14
H
OMe
H
OMe
2
+
2
2
+
N
SmI2
O
N
O
8
N
N
OH
15a
O
O
THF, H2O
OH
OH
15b
OH
15c
OH
OH
°
–
78 C, 2 h
Entry
14 (equiv)
SmI2 (equiv)
H2O (equiv)
Yielda (%)
Reduced product (%)
Pinacolic product (%)
1
2
3
4
2.0
2.0
2.0
5.0
2.0
3.0
3.0
3.0
10.0
10.0
15.0
20.0
60
70
80
89
15
5
0
w10
w10
w10
w10
0
a
Isolated yield (15aþ15bþ15c).

6660
H.-K. Zhang et al. / Tetrahedron 68 (2012) 6656e6664
determined by converting them into the corresponding known
bicyclic compounds 12/13, and further confirmed by the syntheses
of the targets 4/5 in subsequent transformations.
4. Experimental
4.1. General
To prepare indolizidinone derivatives 12/13 from mixture 15,
a hydrogenolysisecyclization procedure was conducted (Scheme 3).
When the diastereomeric mixture of 15 was subjected to Raney-Ni
catalyzed hydrogenolytic conditions at room temperature for 6 h,
complex products were observed. Encouragingly, it was found that
during the work up procedure, to heat the reaction mixture led to an
increasing amount of the desired products 12/13. Thus, after the
Raney-Ni catalyzed hydrogenolysis, the reaction mixture was
heated torefluxin ethanolfor 6 h. In sucha manner, a mixture, which
Optical rotations were recorded on a PerkineElmer 341 auto-
matic polarimeter. 1H NMR spectra were recorded in CDCl3 on
a Bruker 400 spectrometer with Me4Si as an internal standard.
Chemical shifts are expressed in d
(parts per million) units. 13C NMR
spectra were determined at 100 MHz. IR spectra were recorded on
a Nicolet Avatar 360 RT-IR spectrophotometer. Mass spectra were
recorded on a Bruker Dalton Esquire 3000 plus and Finnigan Mat-
LCQ (ESI direct injection). HRFABMS spectra were recorded on
O
O
HO
OH
H
O
O
H
H
OH
OH
OH
•
1 N HCl
93%
BH3 SMe2
N
N
N
THF
87%
1. Raney Ni, H2
2. EtOH, reflux
O
4
12 (31%)
16
15
−
( )-8a-epi-swainsonine
Work-up
62%
O
O
H
O
O
HO
OH
H
H
•
OH BH3 SMe2
1 N HCl
97%
OH
N
OH
N
N
THF
89%
O
(21%)
13
5
17
(−)-8,8a-di-epi-swainsonine
Scheme 3. Synthesis of (ꢀ)-8a-epi-swainsonine (4) and (ꢀ)-8,8a-di-epi-swainsonine (5).
may be coexist of three lactams was obtained in a combined yield of
62%, from which 12/13 were isolated by flash chromatography on
silica gel in 31% and 21% yield, respectively. Compounds 12/13
exhibited physical properties identical to those reported in the lit-
erature.9e,11b The structures of 12/13 were further confirmed by their
conversion into the known compounds 49/5,9e,f,11 respectively. Re-
duction of indolizidinone 12 with borane dimethyl sulfide complex,
followed by deprotection under acidic conditions produced (ꢀ)-8a-
a Bruker APEX-FTMS apparatus. Elemental analyses were per-
formed using a Vario RL analyzer. Melting points were determined
on a Yanaco MP-500 melting point apparatus and are uncorrected.
Tetrahydrofuran (THF) was distilled prior to use from sodium
benzophenone ketyl. Methylene chloride was distilled from phos-
phorus pentoxide. Silica gel (zhifu, 300e400 mesh) from Yantai
silica gel factory (China) was used for column chromatography,
eluting (unless otherwise mentioned) with ethyl acetate/petroleum
ether (60e90 ꢁC) (EtOAc/PE).
epi-swainsonine 4 {½a D20
ꢂ
ꢀ53.1 (c 1.13, MeOH), lit.9b
½
a 2D0
ꢂ
ꢀ49.8 (c
0.71, MeOH)} in an overall yield of 11.2% over Three steps from
(3S,4R)-8. Following the same procedure, (ꢀ)-8,8a-di-epi-swainso-
4.2. General procedure for the SmI2-mediated reductive
coupling reaction of nitrone (3S,4R)-8 with aromatic ketones
nine 5 {½a 2D0
ꢂ
ꢀ19.2 (c 0.67, MeOH), lit.9e
½
a 2D0
ꢂ
ꢀ18.7 (c 0.55, MeOH)}
was also obtained in an overall yield of 6.6% over Three steps from
nitrone 8. The spectroscopical data of 15a/15b were in good agree-
ment to those reported.9b,c
To a solution of nitrone (3S,4R)-820 (100 mg, 0.64 mmol) in
15 mL THF, an aromatic ketone (0.96 mmol), and degassed water
(0.12 mL, 6.4 mmol) at ꢀ78 ꢁC was added a freshly prepared 0.1 M
19a
3. Conclusions
THF solution of SmI2
(19.2 mL, 1.92 mmol) under a N2 atmo-
sphere. After stirring at ꢀ78 ꢁC for 2 h, the reaction was quenched
with H2O (5 mL) and saturated Na2S2O3 (2 mL). The aqueous layer
was extracted with EtOAc (3ꢃ10 mL). The combined organic phases
were washed with brine (20 mL), dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel to afford diastereomers 9aHeeH
and 9aLeeL.
In summary, an efficient method for the synthesis of poly-
hydroxylated prolinol derivatives 9 by the SmI2-mediated reductive
cross-coupling reaction between (3S,4R)-8 with ketones/aldehydes
has been developed. This coupling reaction gave (3aS,4R,6aR) pol-
yhydroxylated prolinol derivatives 9aee in yields of 85e91% with
high C-4 diastereoselectivity for aromatic ketones, and the cross-
coupling reaction with aliphatic aldehydes gave 9hej and 15 in
65e89% yields. The synthetic utility of this method was demon-
strated by the asymmetric synthesis of (ꢀ)-8a-epi-swainsonine (4)
and (ꢀ)-8,8a-di-epi-swainsonine (5) via the SmI2-mediated re-
ductive cross-coupling of methyl 4-oxo-butanate 14 with chiral
nitrone 8, followed by the intramolecular cyclization and depro-
tection. This procedure for constructing N-containing bicyclic
compound can be extended to synthesize other prolinol
derivatives.
4.2.1. (3aS,4R,6aR)-4-[(S)-1-Hydroxyl-1-phenylethyl]-2,2-dimethyl-
tetrahydro-[1,3] dioxolo[4,5-c]pyrrol-5-ol (9aH) and (3aS,4R,6aR)-4-
[(R)-1-hydroxyl-1-phenylethyl]-2,2-dimethyl-tetrahydro-[1,3]dioxolo
[4,5-c]pyrrol-5-ol (9aL). Following the general procedure 4.2, the
SmI2-mediated reductive coupling reaction of (3S,4R)-8 (100 mg,
0.64 mmol) with acetophenone (115 mg, 0.96 mmol) gave com-
pound 9a (162 mg, combined yield: 91%) as a mixture of two di-
astereomers in 40:60 (9aH/aL) ratio (determined by 1H NMR). A

H.-K. Zhang et al. / Tetrahedron 68 (2012) 6656e6664
6661
pair of the major diastereomer was isolated in pure form by column
pair of the major diastereomer was isolated in pure form by column
chromatography eluted by EtOAc/PE¼1:4. Compound 9aH: a col-
chromatography eluted by EtOAc/PE¼1:4. Compound 9cH: a color-
orless syrup, ½a D20
ꢂ
þ22.7 (c 1.27, CHCl3); IR (film) 3462, 3051, 3092,
less syrup, ½a 2D0
þ18.3 (c 1.2, CHCl3); IR (film) 3465, 2977, 2937,
ꢂ
3058, 3079, 2942, 1142, 1372, 1213, 1172 cmꢀ1; 1H NMR (400 MHz,
2836, 1611, 1511, 1463, 1374, 1249, 1208, 1061 cmꢀ1 1H NMR
;
CDCl3)
d
1.36 (s, 3H, CH3),1.54 (s, 3H, CH3),1.55 (s, 3H, CH3), 2.97 (dd,
(400 MHz, CDCl3)
d
0.68 (dd, J¼7.2, 7.3 Hz, 3H, CH2CH3), 1.36 (s, 3H,
J¼6.4, 11.6 Hz, 1H, CH2), 3.44 (dd, J¼6.1, 11.6 Hz, 1H, CH2), 3.52 (d,
J¼5.0 Hz, 1H, NCH), 4.60e4.68 (m, 1H, NCHCH), 4.85e4.95 (m, 1H,
CH2CH), 7.22e7.29 (m, 1H, AreH), 7.32e7.38 (m, 2H, AreH),
CH3), 1.56 (s, 3H, CH3), 1.81 (qd, J¼7.2, 14.0 Hz,1H, CH2CH3), 1.98 (qd,
J¼7.3, 14.0 Hz, 1H, CH2CH3), 2.97 (dd, J¼6.5, 11.5 Hz, 1H, NCH2), 3.46
(dd, J¼6.2, 11.5 Hz, 1H, NCH2), 3.50 (d, J¼4.9 Hz, 1H, NCH), 4.67 (m,
1H, NCHCH), 4.93 (m, 1H, NCH2CH), 6.85e6.90 (m, 2H, AreH),
7.43e7.48 (m, 2H, AreH); 13C NMR (100 MHz, CDCl3)
d 25.0, 27.4,
28.0, 63.9, 73.8, 79.8 (2C), 80.3, 113.9, 124.8, 126.8, 128.3, 147.0; MS
(ESI, m/z): 280 (MþHþ, 60), 302 (MþNaþ, 100); HRMS calcd for
[C15H21NO4þH]þ: 280.1543; found: 280.1544.
7.29e7.35 (m, 2H, AreH); 13C NMR (100 MHz, CDCl3)
d 25.0, 27.3,
27.9, 55.2, 63.7, 73.5, 77.3, 79.8, 80.5, 113.5, 113.8, 126.0, 136.4, 138.9,
158.3; MS (ESI, m/z): 324 (MþHþ, 10), 346 (MþNaþ, 100); HRMS
calcd for [C17H25NO5þH]þ: 324.1805; found: 324.1808.
Compound 9aL: a colorless syrup, ½a D20
þ3.6 (c 1.6, CHCl3); IR
ꢂ
(film) 3435, 3087, 3059, 3028, 2984, 2936, 1446, 1373, 1211,
Compound 9cL: a colorless syrup, ½a D20
ꢀ8.2 (c 1.0, CHCl3); IR
ꢂ
1159 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.16 (s, 3H, CH3), 1.49 (s, 3H,
(film) 3440, 2970, 2937, 2877, 2837, 1611, 1513, 1462, 1373, 1301,
CH3), 1.68 (s, 3H, CH3), 3.37 (dd, J¼4.9, 11.7 Hz, 1H, CH2), 3.45 (dd,
J¼5.5, 11.7 Hz, 1H, CH2), 3.68 (d, J¼2.9 Hz, 1H, NCH), 4.35 (dd, J¼2.9,
6.2 Hz, 1H, NCHCH), 4.47 (ddd, J¼4.9, 5.5, 6.2 Hz, 1H, CH2CH),
7.22e7.29 (m, 1H, AreH), 7.32e7.39 (m, 2H, Are-H), 7.44e7.52 (m,
1249, 1210, 1087 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
0.71 (dd, J¼7.3,
7.4 Hz, 3H, CH2CH3), 1.16 (s, 3H, CH3),1.50 (s, 3H, CH3), 1.94e2.04 (m,
2H, CH2CH3), 3.28 (dd, J¼4.8, 11.9 Hz, 1H, NCH2), 3.49 (dd, J¼5.4,
11.9 Hz, 1H, NCH2), 3.73 (d, J¼2.6 Hz, 1H, NCH), 3.81 (s, 3H, OCH3);
4.36 (dd, J¼2.6, 6.1 Hz, 1H, NCHCH), 4.47 (ddd, J¼4.8, 5.4, 6.1 Hz, 1H,
NCH2CH), 6.87e6.93 (m, 2H, AreH), 7.29e7.35 (m, 2H, AreH); 13C
2H, AreH); 13C NMR (100 MHz, CDCl3)
d 24.7, 27.4, 29.2, 64.3, 74.8,
78.2, 81.1, 82.2, 112.4, 125.2, 127.0, 128.2, 144.9; MS (ESI, m/z): 280
(MþHþ, 95), 302 (MþNaþ, 100); HRMS calcd for [C15H21NO4þH]þ:
280.1543; found: 280.1544.
NMR (100 MHz, CDCl3)
d 24.7, 27.5, 29.1, 33.4, 55.1, 64.3, 77.4, 78.5,
81.6, 81.7, 112.2, 113.4, 127.0, 134.5, 158.0; MS (ESI, m/z): 346
(MþNaþ, 100); HRMS calcd for [C17H25NO5þH]þ: 324.1805; found:
324.1808.
4.2.2. (3aS,4R,6aR)-4-[(S)-1-Hydroxy-1-(4-methoxyphenyl)ethyl]-
2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-ol (9bH) and
(3aS,4R,6aR)-4-[(R)-1-hydroxy-1-(4-methoxyphenyl)ethyl]-2,2-
dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-ol (9bL). Following
the general procedure 4.2, the SmI2-mediated reductive coupling
reaction of (3S,4R)-8 (100 mg, 0.64 mmol) with 4-
methoxyacetophenone (144 mg, 0.96 mmol) gave compound 9b
(176 mg, combined yield: 89%) as a mixture of two diastereomers in
48:52 (9bH/bL) ratio (determined by 1H NMR). A pair of the major
diastereomer was isolated in pure form by column chromatography
4.2.4. (3aS,4R,6aR)-4-[(S)-1-(4-(Dimethylamino)phenyl)-1-
hydroxyethyl]-2,2-dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-ol
(9dH). Following the general procedure 4.2, the SmI2-mediated
reductive coupling reaction of (3S,4R)-8 (100 mg, 0.64 mmol) with
4-(N,N-dimethylamino)acetophenone (156 mg, 0.96 mmol) gave
compound 9d (185 mg, combined yield: 90%) as a mixture of two
diastereomers in 54:46 (9aH/aL) ratio (determined by 1H NMR). A
pure diastereomer 9dH was isolated from the mixture of two di-
astereomers with eluent EtOAc/PE¼1:4, while pure 9dL failed to be
get by column chromatography on silica gel. Compound 9dH:
eluted by EtOAc/PE¼1:4. Compound 9bH: a colorless syrup, ½a D20
ꢂ
þ19.6 (c 1.7, CHCl3); IR (film) 3436, 2985, 2937, 2836, 1611, 1512,
1461, 1375, 1248, 1209, 1056, 1033, 863 cmꢀ1
;
1H NMR (400 MHz,
a colorless syrup, ½a D20
þ14.6 (c 1.1, CHCl3); IR (film) 3454, 2983,
ꢂ
CDCl3) 1.35 (s, 3H, CH3), 1.53 (s, 3H, CH3), 1.55 (s, 3H, CH3), 3.00
d
3059, 2934, 1614, 1521, 1447, 1373, 1208, 1160, 1057 cmꢀ1; 1H NMR
(dd, J¼5.4, 11.4 Hz, 1H, CH2), 3.46 (dd, J¼6.1, 11.4 Hz, 1H, CH2), 3.50
(d, J¼4.8 Hz, 1H, NCH), 3.79 (s, 3H, OCH3), 4.64 (m, 1H, NCHCH),
4.83e4.90 (m, 1H, CH2CH), 6.84e6.90 (m, 2H, AreH), 7.35e7.40 (m,
(400 MHz, CDCl3) d 1.35 (s, 3H, CH3), 1.54 (s, 3H, CH3), 1.56 (s, 3H,
CH3), 2.93 (s, 6H, NCH3), 3.03 (dd, J¼6.5, 11.1 Hz, 1H, CH2), 3.48 (dd,
J¼6.2,11.1 Hz,1H, CH2), 3.49 (d, J¼5.1 Hz,1H, NCH), 4.60 (ddd, J¼5.4,
6.2, 6.5 Hz, 1H, CH2CH), 4.84 (dd, J¼5.1, 5.4 Hz, 1H, NCHCH), 6.72 (d,
J¼8.4 Hz, 2H, AreH), 7.34 (d, J¼8.4 Hz, 2H, AreH); 13C NMR
2H, AreH); 13C NMR (100 MHz, CDCl3)
d 25.0, 27.3, 27.9, 55.2,63.7,
73.5, 79.8 (2C), 80.5, 113.6, 113.7, 126.0, 138.9, 158.3; MS (ESI, m/z):
310 (MþHþ, 100), 332 (MþNaþ, 40); HRMS calcd for
[C16H23NO5þH]þ: 310.1649; found: 310.1645.
(100 MHz, CDCl3)
d 25.1, 27.4, 27.6, 40.6 (2C), 63.4, 73.4, 79.9, 80.9,
112.4, 113.5, 125.6, 134.4, 149.4; MS (ESI, m/z): 323 (MþHþ, 100),
345 (MþNaþ, 33); HRMS calcd for [C17H26N2O4þH]þ: 323.1965;
found: 323.1959. 1H NMR (400 MHz, CDCl3) for 9dL was charac-
Compound 9bL: a colorless syrup, ½a D20
þ3.8 (c 1.6, CHCl3); IR
ꢂ
(film) 3430, 2981, 2938, 2871, 1612, 1514, 1462, 1373, 1210,
1048 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.18 (s, 3H, CH3), 1.49 (s, 3H,
terized by the coexistence of two diastereomers. d 1.19 (s. 3H, CH3),
CH3), 1.65 (s, 3H, CH3), 3.15 (dd, J¼6.9, 11.7 Hz, 1H, CH2), 3.42 (dd,
J¼5.5, 11.7 Hz, 1H, CH2), 3.63 (d, J¼2.9 Hz, 1H, NCH), 3.81 (s, 3H,
OCH3), 4.36 (dd, J¼2.9, 6.2 Hz, 1H, NCHCH); 4.46 (ddd, J¼5.5, 6.2,
6.9 Hz, 1H, CH2CH), 7.03e7.07 (m, 2H, AreH), 7.35e7.43 (m, 2H,
1.50 (s, 3H, CH3), 1.62 (s, 3H, CH3), 2.93 (s, 3H, NCH3), 2.95 (s, 3H,
NCH3), 3.24 (dd, J¼4.4,11.9 Hz,1H), 3.37 (dd, J¼5.2,11.9 Hz,1H), 3.67
(d, J¼2.6 Hz, 1H), 4.40 (dd, J¼2.6, 6.2 Hz, 1H), 4.44 (m, 1H) 6.72 (d,
J¼8.4 Hz, 2H), 7.30 (d, J¼8.4 Hz, 2H).
AreH); 13C NMR (100 MHz, CDCl3)
d 24.7, 27.4, 29.1, 55.2, 64.1, 74.6,
78.1, 81.2, 82.2, 112.4, 113.5, 126.4, 137.0, 158.4; MS (ESI, m/z): 310
(MþHþ, 100), 332 (MþNaþ, 60); HRMS calcd for [C16H23NO5þH]þ:
310.1649; found: 310.1642.
4.2.5. (3aS,4R,6aR)-4-(Hydroxydiphenylmethyl)-2,2-dimethyl-tetra-
hydro-[1,3] dioxolo[4,5-c]pyrrol-5-ol (9e). Following the general
procedure 4.2, the SmI2-mediated reductive coupling reaction of
(3S,4R)-8 (100 mg, 0.64 mmol) with benzophenone (175 mg,
0.96 mmol) gave a single diastereomer 9e (186 mg, 85% yield) with
eluent EtOAc/PE¼1:4 as a white solid. Mp 120e122 ꢁC (EtOAc/PE),
4.2.3. (3aS,4R,6aR)-4-[(S)-1-Hydroxy-1-(4-methoxyphenyl)propyl]-
2,2-dimethyl-tetra hydro-[1,3]dioxolo[4,5-c]pyrrol-5-ol (9cH) and
(3aS,4R,6aR)-4-[(R)-1-hydroxy1-(4-methoxyphenyl)propyl]-2,2-
dimethyl-tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-ol (9cL). Following
the general procedure 4.2, the SmI2-mediated reductive coupling
reaction of (3S,4R)-8 (100 mg, 0.64 mmol) with 1-(4-
methoxyphenyl)propan-1-one (157 mg, 0.96 mmol) gave com-
pound 9c (180 mg, combined yield: 87%) as a mixture of two di-
astereomers in 52:48 (9aH/aL) ratio (determined by 1H NMR). A
½
a 2D0
ꢂ
ꢀ23.5 (c 1.0, CHCl3); IR (film) 3434, 3060, 2987, 2937, 1491,
1.18
1450, 1381, 1212, 1085, 1064 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
(s, 3H, CH3), 1.56 (s, 3H, CH3), 3.11e3.18 (m, 1H, CH2), 3.40e3.48 (m,
1H, CH2), 4.43 (d, J¼1.8 Hz, 1H, NCH), 4.45e4.51 (m, 2H, OCHOCH),
7.14e7.22 (m, 2H, AreH), 7.26e7.34 (m, 4H, AreH), 7.52e7.57 (m,
4H, AreH); 13C NMR (100 MHz, CDCl3)
d
25.2, 27.6, 63.1, 76.4, 77.7,
80.0, 81.3, 112.6, 125.7, 125.8, 126.8, 127.0, 128.3 (2C), 144.1, 146.2;

6662
H.-K. Zhang et al. / Tetrahedron 68 (2012) 6656e6664
MS (ESI, m/z): 342 (MþHþ, 100), 364 (MþNaþ, 40); HRMS calcd for
[C20H23NO4þNa]þ: 364.1525; found: 364.1527.
1471, 1382, 1528, 1210, 1087, 772 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
0.96 (d, J¼6.7 Hz, 3H, CHCH3), 1.07 (d, J¼6.6 Hz, 3H, CHCH3), 1.31
(s, 3H, CH3), 1.52 (s, 3H, CH3), 1.78e1.88 (m, 1H, CHCH3), 3.04 (dd,
J¼5.8, 10.0 Hz, 1H, NCH2), 3.15 (dd, J¼2.2, 5.4 Hz, 1H, NCH), 3.54 (m,
1H, CHOH), 3.65 (dd, J¼6.0, 10.0 Hz, 1H, NCH2), 4.53 (m, 1H, CH2CH),
4.61 (dd, J¼5.4, 6.7 Hz, 1H, NCHCH); 13C NMR (100 MHz, CDCl3)
4.3. GeneralprocedurefortheSmI2-mediated reductive coupling
reaction of nitrone (3S,4R)-8 with aliphatic ketones (or aliphatic
aldehydes)
d
18.7, 19.5, 24.9, 27.1, 30.9, 63.1, 73.6, 74.7, 75.7, 113.3; MS (ESI, m/z):
To a solution of nitrone (3S,4R)-8 (100 mg, 0.64 mmol) in 15 mL
THF, aliphatic ketone (or aliphatic aldehyde) (1.28 mmol) and
degassed water (0.12 mL, 6.4 mmol) at ꢀ78 ꢁC was added freshly
prepared 0.1 M THF solution of SmI2 (12.8 mL, 1.28 mmol) under
a N2 atmosphere. After stirring at ꢀ78 ꢁC for 2 h, the reaction was
quenched with H2O (5 mL) and saturated Na2S2O3 (2 mL). The
aqueous layer was extracted with EtOAc (3ꢃ10 mL). The combined
organic phases were washed with brine (20 mL), dried over anhy-
drous Na2SO4, filtered and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel to afford the
coupling products 9fej.
232 (MþHþ, 100); HRMS calcd for [C11H21NO4þH]þ: 232.1543;
found: 232.1540.
4.3.4. (3aS,4S,6aR)-4-(1-Hydroxy-2,2-dimethylpropyl)-2,2-dimethyl-
tetrahydro-[1,3]dioxolo[4,5-c]pyrrol-5-ol (9j). Following the general
procedure 4.3, the SmI2-mediated reductive coupling reaction of
nitrone 8 (100 mg, 0.64 mmol) with pivalaldehyde (110 mg,
1.28 mmol) gave compound 9j (102 mg, combined yield: 65%) as
a mixture of three diastereomers in 62:29:9 ratio (determined by
1H NMR). The major diastereomer (Rf 0.58, EtOAc/PE¼1:3) was
isolated from the mixture by column chromatography eluted by
EtOAc/PE¼1:4 as a colorless syrup. IR (film) 3316, 2957, 2872, 1482,
4.3.1. (3aS,4R,6aR)-4-(1-Hydroxycyclohexyl)-2,2-dimethyl-tetrahy-
dro-[1,3] dioxolo[4,5-c]pyrrol-5-ol (9f). Following the general pro-
cedure 4.3, but using inversed addition protocol, namely, nitrone 8
(100 mg, 0.64 mmol) was added to a mixture of cyclohexanone
(125 mg, 1.28 mmol) and the SmI2 (1.28 mmol). The reductive
coupling reaction gave compound 9f (69 mg, combined yield: 42%)
as a mixture of two inseparable diastereomers 9fH (major di-
astereomer) and 9fL (minor diastereomer) in 83:17 ratio (de-
termined by 1H NMR) (eluent: EtOAc/PE¼1:4) as a colorless syrup.
1466, 1381, 1210, 1085, 1017, 863 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
1.01 (s, 9H, C(CH3)3), 1.32 (s, 3H, CH3), 1.54 (s, 3H, CH3), 3.17e3.22
(m, 2H), 3.22e3.49 (m, 2H), 4.59 (m, 1H, NCH2CH), 4.85 (m, 1H,
NCHCH); 13C NMR (100 MHz, CDCl3)
d 24.4, 26.0, 27.1, 35.2, 62.8,
75.4, 78.1, 80.2, 84.1, 113.3; MS (ESI, m/z): 246 (MþHþ, 100), 268
(MþNaþ, 27); HRMS calcd for [C12H23NO4þH]þ: 246.1700; found:
246.1701.
4.4. (lS,2R,8R,8aS)-8-Hydroxy-1,2-(iso-propylidenedioxy)
octahydro-5-indolizidinone (12) and (lS,2R,8S,8aS)-8-hydroxy-
1,2-(iso-propylidenedioxy)octahydro-5-indolizidinone (13)
IR (film) 3371, 2934, 2858, 1381, 1209, 1084 cmꢀ1
;
1H NMR
(400 MHz, CDCl3, two isomers)
d 1.32 (s, 3H, CH3, for major isomer),
1.53 (s, 3H, CH3, for major isomer), 1.19e1.82 (m, 10H, (CH2)5), 3.09
(d, J¼5.1 Hz, 1H, NCH, for major isomer), 3.11 (dd, J¼5.9, 11.7 Hz, 1H,
NCH2), 3.57 (dd, J¼5.9, 11.0 Hz, 1H, NCH2, for major isomer),
To a solution of (3S,4R)-8 (188 mg, 1.2 mmol), methyl 4-oxo-
butanoate 14 (696 mg, 6.0 mmol), and degassed water (20 equiv) in
THF was added freshly prepared 0.1 M THF solution of SmI2 (30 mL,
3.0 mmol) at ꢀ78 ꢁC. After stirring at ꢀ78 ꢁC for 2 h under N2, the
reaction was quenched with H2O (5 mL) and saturated Na2S2O3
aqueous (1 mL). Organic phase was separated, and the aqueous
layer was extracted with EtOAc (3ꢃ20 mL). The combined organic
phases were washed with brine (20 mL), dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. The residue was puri-
fied by flash chromatography on silica gel (eluent: EtOAc/PE¼2:1),
affording product 15 (294 mg, combined yield: 89%) as a mixture of
three diastereomers in 50:41:9 ratio (determined by 1H NMR).
Without isolation, the mixture 15 (290 mg, 1.05 mmol) was dis-
solved in 10 mL of EtOH, and Raney-Ni (200 mg) was added. The
mixture was stirred under an atmosphere of hydrogen at room
temperature overnight. Then, another 10 mL of EtOH was added,
and refluxed for 3 h. The mixture was filtered, and the filter residue
was washed with EtOH (5ꢃ10 mL). The combined filtrates were
concentrated in vacuo. The residue was purified by flash chroma-
tography on silica gel (eluent: MeOH/EtOAc/PE¼1:10:10) to give
pure diastereomers 12 (74 mg, 31%) and 13 (50 mg, 21%). Product
4.61e4.82 (m, 2H, OCHOCH); 13C NMR (100 MHz, CDCl3)
d 21.5 (2C),
21.6 (2C), 21.7 (2C), 25.0 (2C), 25.6 (2C), 27.3 (2C), 34.4, 36.2 (2C),
64.6, 71.6 (2C), 72.8, 79.7 (2C), 113.5; MS (ESI, m/z): 258 (MþHþ,
100); HRMS calcd for [C13H23NO4þH]þ: 258.1700; found: 258.1705.
4.3.2. (3aS,4S,6aR)-4-(1-Hydroxybutyl)-2,2-dimethyl-tetrahydro-
[1,3]dioxolo [4,5-c]pyrrol-5-ol (9h). Following the general pro-
cedure 4.3, the SmI2-mediated reductive coupling reaction of
nitrone 8 (100 mg, 0.64 mmol) with n-butyraldehyde (92 mg,
1.28 mmol) gave compound 9h (106 mg, combined yield: 72%) as
a mixture of three diastereomers in 51:32:17 ratio (determined by
1H NMR). The major diastereomer (Rf 0.42, EtOAc/PE¼1:3) was
isolated from the mixture by column chromatography eluted by
EtOAc/PE¼1:4 as a colorless syrup. IR (film) 3312, 2954, 2934, 2867,
1375, 1205, 1080, 860 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 0.96 (t,
J¼7.1 Hz, 3H, CH2CH3), 1.31 (s, 3H, CH3), 1.52 (s, 3H, CH3), 1.24e1.66
(m, 4H, CH2CH2), 2.91 (dd, J¼1.6, 5.0 Hz, 1H, NCH), 3.01 (dd, J¼6.0,
10.0 Hz, 1H, NCH2), 3.63 (dd, J¼6.1, 10.0 Hz, 1H, NCH2), 3.93e4.00
(m, 1H, CHOH), 4.53 (m, 1H, NCH2CH), 4.62 (dd, J¼5.0, 6.5 Hz, 1H,
NCHCH); 13C NMR (100 MHz, CDCl3)
d
14.0, 19.3, 24.9, 27.1, 62.9,
12: a white solid, Mp 136e138 ꢁC (EtOAc) {lit.11b 132e135 ꢁC}; ½a 2D5
ꢂ
67.5, 72.5, 75.5, 76.2, 77.1, 113.4; MS (ESI, m/z): 232 (MþHþ, 40), 254
(MþNaþ, 100); HRMS calcd for [C11H21NO4þH]þ: 232.1543; found:
232.1541.
ꢀ38.5 (c 1.50, CHCl3) {lit.9e
½
a 2D0
ꢂ
þ30.0 (c 1.2, CHCl3), for antipode of
12}; IR (film) 3347, 2985, 2936, 1620, 1461, 1374, 1215, 1085 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d 1.37 (s, 3H, CH3), 1.53 (s, 3H, CH3),
1.85e1.96 (m, 1H, CHOHCH2), 2.03e2.12 (m, 1H, CHOHCH2), 2.33
(dd, J¼6.4, 18.5 Hz, 1H, NCOCH2), 2.49 (ddd, J¼7.2, 11.7, 18.5 Hz, 1H,
NCOCH2), 3.29 (br s, 1H, OH), 3.47 (d, J¼13.7 Hz, 1H, NCH2), 3.51 (dd,
J¼2.1, 6.3 Hz, 1H, NCH), 4.14 (dd, J¼6.1, 13.7 Hz, 1H, NCH2), 4.32 (m,
1H, CHOH), 4.69 (ddd, J¼2.1, 6.1, 6.3 Hz, 1H, NCH2CH), 4.84 (dd,
4.3.3. (3aS,4S,6aR)-4-(1-Hydroxy-2-methylpropyl)-2,2-dimethyl-tet-
rahydro-[1,3] dioxolo[4,5-c]pyrrol-5-ol (9i). Following the general
procedure 4.3, the SmI2-mediated reductive coupling reaction of
nitrone 8 (100 mg, 0.64 mmol) with iso-butyraldehyde (92 mg,
1.28 mmol) gave compound 9i (118 mg, combined yield: 80%) as
a mixture of three diastereomers in 54:33:13 ratio (determined by
1H NMR). The major diastereomer (Rf 0.46, EtOAc/PE¼1:3) was
isolated from the mixture by column chromatography eluted by
EtOAc/PE¼1:4 as a colorless syrup. IR (film) 3318, 2960, 2937, 2872,
J¼6.2, 6.3 Hz, 1H, NCHCH); 13C NMR (100 MHz, CDCl3)
d 25.6, 25.9,
27.8, 28.2, 49.6, 62.3, 66.9, 76.5, 79.5, 113.1, 169.0; MS (ESI, m/z): 228
(MþHþ, 20), 250 (MþNaþ, 100); HRMS calcd for [C11H17NO4þNa]þ:
250.2501; found: 250.2505. Product 13: a colorless oil, ½a D20
ꢀ31.0 (c
ꢂ
1.25, CHCl3) {lit.9e
[
a]
ꢀ26.2 (c 1.7, CHCl3)}; IR (film) 3390, 2935,
D

H.-K. Zhang et al. / Tetrahedron 68 (2012) 6656e6664
6663
1621, 1453, 1382, 1215, 1085 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.37
½
a 2D0
ꢂ
ꢀ53.1 (c 1.13, MeOH) {lit.9e
½
a 2D0
ꢂ
ꢀ49.8 (c 0.71, MeOH)}; IR
(s, 3H, CH3), 1.57 (s, 3H, CH3), 1.76e1.98 (m, 1H, CHOHCH2),
2.07e2.16 (m, 1H, CHOHCH2), 2.39 (ddd, J¼6.7, 11.7, 18.2 Hz, 1H,
NCOCH2), 2.55 (ddd, J¼1.9, 6.7, 18.2 Hz, 1H, NCOCH2), 3.01 (br s, 1H,
OH), 3.36 (dd, J¼6.5, 9.0, 1H, NCH), 3.42 (dd, J¼2.3, 13.7 Hz, 1H,
NCH2), 3.73 (ddd, J¼1.9, 9.0, 11.7 Hz, 1H, CHOH), 4.20 (dd, J¼6.5,
13.7 Hz, 1H, NCH2), 4.51 (dd, J¼6.5, 6.7 Hz, 1H, NCHCH), 4.74 (ddd,
(film) 3354, 2930, 2820, 1360, 1157, 1052 cmꢀ1; 1H NMR (400 MHz,
D2O)
d 1.39e1.52 (m, 2H, NCH2CH2), 1.58e1.71 (m, 1H, CHOHCH2),
1.75e1.83 (m, 1H, CHOHCH2), 2.00e2.11 (m, 3H), 2.86 (d, J¼10.8 Hz,
1H, NCH2CH), 3.31 (dd, J¼6.8, 10.8 Hz, 1H, NCH2CH), 3.81 (dd, J¼7.0,
9.0 Hz, 1H, CHOH), 3.97e4.07 (m, 2H, NCH2CHCH); 13C NMR
(100 MHz, D2O) d 19.5, 30.2, 52.9, 60.7, 63.7, 67.1, 69.7, 69.9; MS (ESI,
J¼2.3, 6.5, 6.7 Hz, 1H, NCH2CH); 13C NMR (100 MHz, CDCl3)
d
25.5,
m/z): 174 (MþHþ, 93), 196 (MþNaþ, 100).
27.7, 29.6, 29.8, 49.4, 67.9, 69.8, 76.8, 84.0,114.1,168.1; MS (ESI, m/z):
228 (MþHþ, 80), 250 (MþNaþ, 100); HRMS calcd for
[C11H17NO4þNa]þ: 250.2501; found: 250.2504.
4.8. (lS,2R,8S,8aS)-Octahydro-1,2,8-indolizidinetriol [(L)-8,8a-
di-epi-swainsonine] (5)
4.5. (lS,2R,8R,8aS)-8-Hydroxy-1,2-O-iso-propylideneoctahydro-
1,2,8-indolizidine triol (16)
Following the procedure 4.7, compound 5 was prepared from
(1S,2R,8S,8aS)-l,2-O-iso-propylideneoctahydro-l,2,8-indolizidine-
triol (17) as a white solid (22 mg, 97% yield). Mp 128e130 ꢁC
a 20
a 29
ꢀ14.0 (c
(MeOH) (lit.9e 129e130 C); ½ ꢂD ꢀ19.2 (c 0.67, MeOH) {lit. ½ ꢂD
ꢁ
To a solution of (lS,2R,8R,8aS)-8-hydroxy-1,2-(iso-propylidene-
dioxy) octahydro-5-indolizidinone (12) (50 mg, 0.22 mmol) in THF
(5 mL) was added BH3$SMe2 (2.2 mmol, 0.21 mL). After stirring at
room temperature for 4 h, the reaction was carefully quenched by
adding EtOH (3 mL). After removal of the solvent, the residue was
dissolved in EtOH (5 mL) and refluxed for 2 h. The solvent was
removed, and the residue was purified by flash chromatography on
silica gel (eluent: EtOH/EtOAc¼1:9) to give 16 (42 mg, 89%) as
ꢀ13.2 (c 0.27, MeOH),11a
½
a 2D0
ꢂ
ꢀ18.7 (c 0.55, MeOH),9e
½
a 2D5
ꢂ
0.51, MeOH),9f
½
a 2D2
ꢂ
ꢀ21.2 (c 0.78, MeOH)11b}; IR (film) 3351, 2930,
2819, 1362, 1261 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 1.14e1.25 (m,
1H, NCH2CH2), 1.33e1.46 (m, 1H, NCH2CH2), 1.59e1.68 (m, 1H,
CHOHCH2),1.87 (dd, J¼8.4, 8.9 Hz,1H, CHOHCH2),1.88e2.05 (m, 2H,
NCH2CH2), 2.14 (dd, J¼6.3, 10.3 Hz, 1H, NCH2CH), 2.78 (d, J¼11.2 Hz,
1H, NCH), 3.27 (dd, J¼6.9, 10.3 Hz, 1H, NCH2CH), 3.40 (ddd, J¼4.4,
6.9,10.3 Hz,1H, CHOH), 3.80 (dd, J¼7.5, 7.7 Hz,1H, NCH2CHCH), 4.05
(ddd, J¼6.3, 6.7, 6.9 Hz, 1H, NCH2CH); 13C NMR (100 MHz, CDCl3)
a colorless syrup: ½a D20
ꢂ
ꢀ51.2 (c 1.30, CHCl3) {lit.9d
½
a 2D0
ꢂ
ꢀ48.8 (c 0.5,
CHCl3)}; IR (film) 3590, 2930, 1340, 1050 cmꢀ1; 1H NMR (400 MHz,
CDCl3)
d 1.34 (s, 3H, CH3), 1.38e1.52 (m, 2H, NCH2CH2), 1.51 (s, 3H,
d
22.4, 32.0, 50.4, 58.7, 66.5, 70.5, 71.3, 73.0; MS (ESI, m/z): 174
(MþHþ, 100).
CH3), 1.65e1.83 (m, 1H, CHOHCH2), 1.89 (d, J¼8.1 Hz, 1H, CHOHCH2),
2.17 (dd, J¼2.9, 11.1 Hz, 1H, NCH2CH2), 2.22 (d, J¼5.4 Hz 1H,
NCH2CH2), 2.34 (dd, J¼5.3, 9.3 Hz, 1H, NCH), 2.48 (m, 1H, OH), 2.93
(dd, J¼3.8, 10.7 Hz, 1H, NCH2CH), 3.38 (dd, J¼6.3, 9.3 Hz, 1H, CHOH),
4.04 (m, 1H, NCH2CH), 4.55e4.68 (m, 2H, NCH2CHCH); 13C NMR
Acknowledgements
The authors are grateful to the NSF of Fujian, China (Grant No.
20672089) for financial support and the program for Innovative
Research Team in Science & Technology (University) in Fujian
Province is gratefully acknowledged.
(100 MHz, CDCl3)
d 19.1, 25.0, 27.1, 30.8, 52.3, 60.3, 64.6, 72.3, 77.0,
79.7, 113.8; MS (ESI, m/z): 214 (MþHþ, 95), 236 (MþNaþ, 100).
4.6. (lS,2R,8S,8aS)-8-Hydroxy-1,2-O-iso-propylideneoctahydro-
1,2,8-indolizidine triol (17)
References and notes
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Following the procedure 4.5, compound 17 was prepared from
(lS,2R,8S,8aS)-8-hydroxy-1,2-(iso-propylidenedioxy)octahydro-5-
indolizidinone (13) as a colorless syrup in a yield of 90%. ½a D20
ꢀ23.8
ꢂ
(c 1.00, CHCl3) {lit.11b
½
a 2D2
ꢂ
ꢀ29.6 (c 1.14, CHCl3)}; IR (film) 3600,
2940, 1640, 1450, 1375, 1210, 1080 cmꢀ1; 1H NMR (400 MHz, CDCl3)
1.18e1.30 (m, 1H, NCH2CH2), 1.35 (s, 3H, CH3), 1.53 (s, 3H, CH3),
d
1.47e1.60 (m, 1H, NCH2CH2), 1.66e1.74 (m, 1H, CHOHCH2), 1.97 (dd,
J¼5.9, 9.0 Hz, 1H, CHOHCH2), 2.03e2.11 (m, 2H, NCH2CH2), 2.13 (dd,
J¼2.8, 11.7 Hz, 1H, CHOHCH2), 2.40 (dd, J¼5.3, 9.3 Hz, 1H, OH), 2.88
(d, J¼10.8 Hz, 1H, NCH2CH), 3.39 (dd, J¼6.4, 9.3 Hz, 1H, CHOH), 3.47
(ddd, J¼4.5, 9.3, 10.8 Hz, 1H, NCH2CH), 4.47 (dd, J¼6.1, 7.1 Hz, 1H,
NCHCH), 4.70 (ddd, J¼5.6, 6.5, 6.5 Hz, 1H, NCH2CH); 13C NMR
4. (a) Goeminne, A.; Berg, M.; McNaughton, M.; Bal, G.; Surpateanu, G.; Van der
ꢀ
(100 MHz, CDCl3)
d
23.7, 25.0, 27.1, 33.6, 51.2, 59.7, 71.3, 74.4, 77.5,
Veken, P.; De Prol, S.; Versees, W.; Steyaert, J.; Haemers, A.; Augustyns, K. Bi-
83.5, 114.4; MS (ESI, m/z): 214 (MþHþ, 100).
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Van der Veken, P.; De Prol, S.; Versees, W.; Steyaert, J.; Haemers, A.; Augustyns,
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epi-swainsonine] (4)
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A solution of the compound 16 (24.0 mg, 0.113 mmol) in 1 N HCl
(2 mL) was refluxed for 30 min. After being cooled to room tem-
perature, the mixture was concentrated. The residue was dissolved
in MeOH (3 mL) and 6 N HCl (0.5 mL) was added. The mixture was
stirred at room temperature for 30 min and then concentrated. The
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exchanged resin (Dowex 1ꢃ8e100, OHꢀ form) eluting with water
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raphy
on
silica
gel,
(eluent:
NH4OH/n-BuOH/EtOH/
CH2C12¼1:3:3:3) to give (ꢀ)-8a-epi-swainsonine (4) (19.0 mg, 93%
yield) as a white solid. Mp 117e119 ꢁC (MeOH) {lit.9f 116e118 ꢁC};

6664
H.-K. Zhang et al. / Tetrahedron 68 (2012) 6656e6664
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