A diastereoselective cyclic imine cycloaddition strategy to access polyhydroxylated indolizidine skeleton: Concise syntheses of (+)-/(-)-lentiginosines and (-)-2-epi-steviamine

Article abstract of DOI:10.1021/jo3010777

We describe in this paper the development of a novel diastereoselective cyclic imine cycloaddition strategy to access the polyhydroxylated indolizidine skeleton and its application in the concise syntheses of (+)-/(-)-lentiginosines and (-)-2-epi-steviamine.

Full text of DOI:10.1021/jo3010777

Subscriber access provided by UNIVERSITY OF SASKATCHEWAN LIBRARY
Article
A Diastereoselective Cyclic Imine Cycloaddition Strategy
to Access Polyhydroxylated Indolizidine Skeleton: Concise
Syntheses of (+)-/(–)-Lentiginosines and (–)-2-epi-Steviamine
Jia Shao, and Jinsong Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo3010777 • Publication Date (Web): 04 Sep 2012
Downloaded from http://pubs.acs.org on September 9, 2012
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 36
The Journal of Organic Chemistry
1
2
3
4
A Diastereoselective Cyclic Imine Cycloaddition Strategy to Access Polyhydroxylated
5
6
7
Indolizidine Skeleton: Concise Syntheses of (+)ꢀ/(–)ꢀLentiginosines and (–)ꢀ2ꢀepiꢀSteviamine
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Jia Shao and Jinsong Yang*
Key Laboratory of Drug Targeting, Ministry of Education, and Department of Chemistry of Medicinal
Natural Products, West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. China
Corresponding author. E-mail address: yjs@scu.edu.cn, yjscd@163.com (J.ꢀS. Yang).
Graphic Abstract
OR1
R1O
OR2
H
N
TMSO
O
Yb(OTf)3 (0.5 eq.)
CH2Cl2, –40→0 °C
up to 73% yield
up to >99:1 d.r.
OR2
N
OMe
OH
OH
H
N
OH
OH
H
N
H
OH
OH
N
OH
2ꢀepiꢀ(ꢀ)ꢀSteviamine
(+)ꢀLentiginosine
(ꢀ)ꢀLentiginosine
ABSTRACT: We describe in this paper the development of a novel diastereoselective cyclic imine
cycloaddition strategy to access polyhydroxylated indolizidine skeleton, and its application in the
concise syntheses of (+)ꢀ/(–)ꢀlentiginosines and (–)ꢀ2ꢀepiꢀsteviamine.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 36
1
2
3
4
INTRODUCTION
5
6
7
8
9
Polyhydroxylated indolizidine alkaloids (iminosugars or azasugars), a series of sugar mimics such as
lentiginosine (1), swainsonine (2), and castanospermine (3) (Figure 1), and their stereoisomers are
widespread in plants and microorganisms.1 Their intriguing structure combined with their potent
ability to inhibit glycosidases as well as for the anticancer, antiꢀHIV, and immunoregulatory
activities2 have inspired considerable synthetic efforts directed both at the naturallyꢀoccurring
compounds such as 1–3,3 and at the structurally related analogues for pharmacological evaluation.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Natural Polyhydroxylated Indolizidines
OH
OH
OH
OH
(ꢀ)ꢀSwainsonine (2)
OH
OH
OH
H
N
H
H
HO
HO
N
N
(+)ꢀLentiginosine (1)
(+)ꢀCastanospermine (3)
So far, several conceptual synthetic approaches have been adopted in this field, namely a chiral pool,
an enantioꢀ, and a diastereoselective approaches.5–7 The first method typically employs natural
carbohydrates as starting material and introduces the ring nitrogen through their manipulation, thereby
often leading to lengthy synthetic sequences and lacking enough flexibility for the preparation of a
wide range of derivatives. On the other hand, up to date, a variety of the latter two strategies have
been devised and applied successfully in the synthesis of polyhydroxyindolizidineꢀbased compounds.
However, most of the published methods rely on a linear and multiꢀstep procedure consisting of
forming either the fiveꢀ or sixꢀmembered pyrrolidine or piperidine unit and followed later by
installing the second ring through intramolecular cyclization to construct the indolizidine bicyclic core.
Although a convergent strategy depending on the 1,3ꢀdipolar cycloaddition of chiral nitrones with
2
ACS Paragon Plus Environment

Page 3 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
olefins was utilized by both Brandi6,8 and Tamayo4o groups to synthesize 1 and other indolizidine
iminosugars, the formation of the indolizidine skeleton still requires further elaboration of the primary
cycloadducts. Moreover, despite the fact that the intramolecular thermal imino Diels–Alder9 and
double ring closure reactions3p,10 were developed to provide a direct entry into the indolizidine bicycle,
the former suffers from the poor cycloaddition stereoselectivity and the harsh highꢀtemperature
activation conditions while the latter is confined to parallel syntheses of the target molecules.
Therefore, the development of a more reliable and facile synthetic methodology, especially a useful
solution to address the problem associated with indolizidine ring construction is still desirable for the
synthesis of this biologically important class of natural products.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The retrosynthetic plan we intended to use for this goal is illustrated in Scheme 1. We envisioned that
the target indolizidine could be gained from hydroxyindolizidine enaminone 4 via a sequence of
functional group transformations.11 In turn, the crucial indolizidine scaffold would be generated in a
convergent fashion from an intermolecular [4+2] azaꢀDiels–Alder reaction of electronꢀrich
Danishefskyꢀtype silyloxydienes 5 and oxygenated fiveꢀmembered aldimine ring 6. The latter was
proposed to originate from cheap and commercially available chiral compounds. If this cycloaddition
process worked well, in particular if the stereochemistry of the bridgehead C8a position could be
rigorously controlled, the method would serve as a straightforward and general route to the
polyhydroxylated indolizidine as it not only builds up the technically challenging indolizidine
5,6ꢀfused ring system in a single operation, but also allows various indolizidine iminosugars and
analogues to be produced from a common pathway.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 36
1
2
3
4
Scheme 1. Retrosynthetic Strategy
5
6
7
H
(OPG)n
(OPG)n
TMSO
O
Polyhydroxylated
Indolizidines
R
N
N
8
9
4
OMe
6
aza-Diels-Alder
Reaction
5a R = H
5b R = Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
PG: protecting group
Tartaric and malic acids,
Furanoses
The asymmetric azaꢀDiels–Alder reaction has long proven an invaluable aid in giving access to the
highly functionalized sixꢀmembered nitrogenꢀcontaining heterocycles.12 In contrast to the intensive
study on the acyclic imineꢀparticipated azaꢀDiels–Alder reactions, very few examples were devoted so
far to the aboveꢀmentioned cycloaddition version employing unactivated cyclic imine as dienophile.13
The synthetic value held by such type of cyclocondensation reaction has been outlined by the
pioneering works of Vacca, Danishefsky, and Weinreb in the rapid synthesis of yohimbine
derivatives14 and racemic indolizidine alkaloid ipalbidine,15 and in the assembly of the A ring portion
of tetracyclic alkaloid phyllanthine,16 respectively. More recently, the power of the cyclic imine [4+2]
annulation strategy was also exemplified by Gin et al. in their elegant creation of the complex tricyclic
core structure of the batzelladine alkaloids.17 Here, we wish to present the use of flexible, unactivated,
and optically active ꢀ1ꢀpyrroline species as coupling partners to achieve a highly diastereoselective
azaꢀDiels–Alder cycloaddition en route to a range of bicyclic hydroxyindolizidinones, in which the
C8a stereogenic center is efficiently established in a substrateꢀstereocontrolled manner. Furthermore,
the synthetic potential of this new method is demonstrated with the short total synthesis of three
natural
and
nonꢀnatural
polyhydroxylated
indolizidines
(+)ꢀ/(–)ꢀlentiginosines
and
(–)ꢀ2ꢀepiꢀsteviamine.
4
ACS Paragon Plus Environment

Page 5 of 36
The Journal of Organic Chemistry
1
2
3
4
RESULTS AND DISCUSSION
5
6
7
8
9
We began our studies by investigating the model cycloaddition reaction of the known
transꢀ(3S,4S)ꢀdiꢀOꢀTBS protected pyrrolidine imine 6a18 with an excess of diene 5a under a range of
conditions, which mainly focused on varying the nature of the catalyst and solvent (Table 1).
Eventually, use of a stoichiometric amount of zinc chloride as catalyst in THF afforded indolizidinone
cycloadducts 4a and 4a′ as a 1.9:1 mixture of separable diastereomers at C8a in favour of 4a (36%
yield) with a trans arrangement for H1 and H8a (Table 1, entry 1). A similar trend was observed in
toluene (Table 1, entry 2). The isolated yield (65%) of 4a was improved in CH2Cl2 but the d.r. value
was still unsatisfactory (Table 1, entry 3; d.r. 4/1). The stereochemical assignment at the ring junction
(C8a) in each of the adducts was firmly established by NOE experiment. In the case of 4a, the NOE
spectrum showed a correlation between protons H2 and H8a, which was evidently absent in the
spectrum of isomeric cisꢀH1/H8a adduct 4a′.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of AzaꢀDiels–Alder Reaction of Diene 5a and Cyclic Imine 6aa
NOE
OTBS
TBSO
OTBS
H
OTBS
OTBS
H
H
TMSO
O
O
N
6a
conditions
8a
N
N
OTBS
5a
4a
4a'
OMe
Entry Catalyst (equiv) T (°C)/Solvent
Yield (%)b
drc
1
2
3
4
5
ZnCl2 (1.0)
ZnCl2 (1.0)
ZnCl2 (1.0)
AlCl3 (1.0)
BF3ꢁEt2O (1.0)
–40 → rt/THF
36
1.9/1
1.2/1
4/1
–40 → rt/toluene
–40 → rt/CH2Cl2
–40/CH2Cl2
43
65
70
4.9/1
n.d.d
–40/CH2Cl2
<15
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 36
1
2
3
4
5
6
7
8
9
6
7
8
AgOTf (1.0)
–40 → rt/CH2Cl2
–40/CH2Cl2
<15
73
n.d.d
11/1
11/1
Yb(OTf)3 (1.0)
Yb(OTf)3 (0.5)
–40 → 0/CH2Cl2
73
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReactions were performed with 5a (3.0 equiv), 6a (1.0 equiv), and catalyst in anhydrous organic
b
c
solvent for 3 h. Isolated yield of the pure diastereomer 4a. Determined by 1H NMR analysis of the
crude reaction mixture. dNot determined.
Using CH2Cl2 as reaction medium, we next turned to probe the effect of catalyst on the reaction.
Changing the catalyst to AlCl3 brought about an improved yield and stereoselectivity (Table 1, entries
4 vs 3). Both BF3ꢁEt2O and AgOTf displayed rather low catalytic activity, affording less than 15%
yield of the expected products (Table 1, entries 5 and 6). Gratifyingly, when one equiv of Yb(OTf)3
was used as catalyst, the reaction gave the highest efficiency in excellent yield and diastereoselectivity
(Table 1, entry 7; 73% yield, d.r. 11/1). In addition, the catalyst loading could be decreased to 0.5
equiv without a loss of reactivity or selectivity (Table 1, entry 8).
With the optimal reaction conditions (0.5 equiv of Yb(OTf)3 in CH2Cl2 at –40 → 0 °C), we set out to
examine a panel of enantiopure hydroxylated cyclic imines entꢀ6a and 6b–f (cf. Figure 2) to establish
the reaction generality.
6
ACS Paragon Plus Environment

Page 7 of 36
The Journal of Organic Chemistry
1
2
3
4
Figure 2. Optically Active FiveꢀMembered Cyclic Imines
5
6
7
OR BocO
RO
BnO
R1O
OR2
OBn
OBn
N
N
N
N
8
9
6b R = Bn
6c R = MOM
6d
entꢀ6a R1 = R2 = TBS
6f R1 = Boc, R2 = TBS
6e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The known cyclic imines entꢀ6a18,19 and 6e20 were prepared according to the literature procedures. As
depicted in Scheme 2, starting from optically active tartaric and malic acids, the other imine substrates
6b–d and 6f were conveniently prepared and characterized as their homochiral trimers 6b′–d′ and
6f′,23 respectively, by the use of the published approach involving Nꢀchlorination of the corresponding
substituted pyrrolidine with Nꢀchlorosuccinimide (NCS)24 and then dehydrochlorination of the
resulting pyrrolidine Nꢀchlorides with 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (DBU).18,25,26 The DBU
dehydroalogenations of pyrrolidine Nꢀchlorides 11 and 15 displayed a complete regioselectivity. In
both cases (Scheme 2, eqs 2 and 3), the eliminations occurred exclusively on the side of the BocO
group since the electronꢀwithdrawing property of Boc functionality increases the acidity of H2,27 thus
giving rise to triazines 6d′ and 6f′ in 70% and 72% yield, respectively. The structures of these
obtained triazine derivatives were confirmed by 1D (1H, 13C, 400 MHz) NMR spectroscopy and ESI
MS. Take compound 6c′ for example. In its 1H NMR spectrum, the H2 protons appear as a doublet at
δH 3.03 ppm (J2,3 = 5.2 Hz), while the 13C NMR spectrum shows a peak at δC 83.0 ppm for C2.
Further support for its structure comes from highꢀresolution ESIꢀTOF MS data, which gives an
(M+Na)+ signal at m/z 590.2905 (calcd 590.2901).
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 36
1
2
3
4
Scheme 2. Synthesis of Optically Active FiveꢀMembered Cyclic Imines
5
6
7
8
OR
RO
N
OR
RO
OR
RO
DBU
Et2O
NCS
Et2O
Ref.21
(1)
L
ꢀTartaric acid
N
N
N
RO
RO
H
N
OR
OR
Cl
7b, R = Bn
8b, R = Bn (90%)
8c, R = MOM (88%)
9
7c, R = MOM
6b', R = Bn (78%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6c', R = MOM (75%)
BocO
R1O
Ref.22
DBU, Et2O
(2)
LꢀMalic acid
N
N
N
70%
N
OBoc
R2
BocO
9, R1 = H, R2 = Bn
10, R1 = Boc, R2 = Bn
11, R1 = Boc, R2 = Cl
6d'
Boc2O, Bu2SnO
K2CO3,THF, 73%
1) H2, Pd/C, CH3OH
2) NCS, Et2O, 60% over 2 steps
OTBS
DBU, Et2O
72%
R1O
BocO
1) H2, Pd/C, CH3OH
OR2
Ref.21b
(3)
D
ꢀTartaric acid
N
2) NCS, Et2O
65% over 2 steps
N
Cl
Bn
15
12, R1 = R2 = H
Boc2O, Bu2SnO,
K2CO3, THF, 81%
OTBS
BocO
13, R1 = Boc, R2 = H
TBSCl, Imidazole,
DMF, 85%
N
N
TBSO
14, R1 = Boc, R2 = TBS
N
OBoc
OTBS
BocO
6f'
As shown in Table 2, cyclic imines 6a–c bearing various protecting groups including silyl (TBS) ether,
benzyl (Bn) ether, and methoxymethyl (MOM) acetal all reacted smoothly with diene 5a,b, affording
predominantly the bicyclic transꢀH1/H8a adducts 4a–c and 4f with reasonable yields and high level of
diastereomeric ratios (Table 2, entries 1–3 and 7). The bulkiness of the oxygenꢀcontaining substitution
close to the imine carbon–nitrogen double bond had a significant effect on the stereochemical
outcome. For example, cycloadditions of the TBSꢀ and Bnꢀprotected 6a and 6b gave greater
diastereoselectivity ratios of 11:1, 10:1, and 11:1, respectively, instead of the 5:1 ratio obtained by
using the MOMꢀprotected 6c (Table 2, entries 1, 2, and 7 vs entry 3).
8
ACS Paragon Plus Environment

Page 9 of 36
The Journal of Organic Chemistry
1
2
3
4
Table 2. Substrate Profilea
5
6
7
8
H
(OPG)n
TMSO
(OPG)n
O
Yb(OTf)3
CH2Cl2
R
N
N
ꢀ40 → 0 °C, 3 h
OMe
4
6
5a R = H
9
5b R = Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry Diene
Imine
Major Product
Yield (%)b drc
OTBS
H
1
5a
6a
73
11:1
O
OTBS
N
4a
4c
OBn
H
O
6bd
6cd
65
62
73
71
63
10:1
5:1
OBn
N
2
3
4
5
6
4b
OMOM
OMOM
H
N
O
O
OBoc
H
N
6dd
entꢀ6a
6e
>99:1
10:1
>99:1
4d
OTBS
H
N
O
O
OTBS
entꢀ4a
OBn
OBn
OBn
H
N
4e
OTBS
OTBS
H
N
O
7
8
9
5b
6a
6e
6fd
70
65
62
11:1
4f
OBn
OBn
OBn
H
O
>99:1
10:1
N
4g
OBoc
OTBS
H
O
N
4h
aReactions were performed with diene (9.0 equiv), imine trimer (1.0 equiv), and Yb(OTf)3 (1.5 equiv)
for entries 2–4, and 9 or with diene (3.0 equiv), imine monomer (1.0 equiv), and Yb(OTf)3 (0.5 equiv)
b
for entries 1, and 5–8 in anhydrous CH2Cl2 at –40 → 0 °C for 3 h. Isolated yield of the pure major
c
d
product. Determined by 1H NMR analysis of the crude reaction mixture. The trimeric imines could
be converted in situ into the corresponding monomeric form under the cycloaddition conditions.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 36
1
2
3
4
5
6
7
8
9
Thus, the C3 stereocenter of the fiveꢀmembered cyclic imine as a key factor in determining the
stereoselectivity was demonstrated. The extent of diastereoselectivity was accordingly influenced by
the size of the C3 hydroxy protecting group. We reasoned that, due to the steric requirement, the
attack of the diene anti to the OR function at C3 position of the imine ring should be preferable over
the possible syn attack (Figure 3). As a result, the larger OH protecting groups will give the better anti
facial preferences.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Diastereoselectivity of the Cycloaddition
OR
4
3
2
5
H
MeO
RO
OTMS
OR
N
RO
1
OTMS
H
N
MeO
antiꢀ
synꢀ
Moreover, the cycloadditions of iminoꢀdienophiles entꢀ6a and 6d–f each having a βꢀsubstituent at C3
position to dienes 5a,b also followed the less sterically hindered anti stereocontrol mode and
furnished indolizidinones entꢀ4a, 4d,e, and 4g,h with identical H1–H8a trans relative configurations
as major Diels–Alder cycloadducts in high chemical yields and good to excellent diastereoselectivities
(Table 2, entries 4–6, 8, and 9). In fact, the bulky 3ꢀOꢀtertꢀbutyloxycarbonyl (Boc)ꢀprotected 6d and
the highly congested 6e derived from Dꢀarabinose are the best cycloaddition building blocks and the
corresponding bicyclic adducts 4d,e, and 4g could be obtained in high yields as single products (Table
2, entries 4, 6, and 8, d.r. >99:1).
10
ACS Paragon Plus Environment

Page 11 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Having realized a practical method to the bicyclic indolizidine enaminones, we then planned to
explore their usefulness as key advanced intermediates for making polyhydroxyindolizidine
iminosugars.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
transꢀ1,2ꢀDihydroxyindolizidine (+)ꢀlentiginosine ((+)ꢀ1), originally extracted by Elbein and
coꢀworkers in 1990 from the leaves of Astragalus lentiginosus, is a potent and selective indolizidine
inhibitor of the fungal
α
ꢀglucosidase and amyloglucosidase.6,28 Interestingly, in recent work by
Macchi and Brandi et al., the nonꢀnatural laevorotatory enantiomer (–)ꢀlentiginosine ((–)ꢀ1) is found
to be able to induce remarkable levels of apoptosis in some tumor cell lines whereas the natural (+)ꢀ1
can not.29 Over the years, being interested in the two enantiomers, the synthetic community made out
of their way to prepare them in greater quantities and to use them as a tool to validate new
methodologies.5,6 We chose lentiginosine as our initial synthetic target since its relatively structural
simplicity would enable us to easily check the basic principles of the developed method. Here, we
describe an alternative synthetic approach to (+)ꢀ and (–)ꢀ1 based on the use of cycloadducts 4a and
entꢀ4a.
The synthesis of (+)ꢀlentiginosine is summarized in Scheme 3. The vinylogous amide moiety of 4a
was hydrogenated over palladiumꢀonꢀcarbon (10%) to a 1:4.5 mixture of 16 and 17, which could be
easily separated by silica gel chromatography (15% and 68% yields from 4a, respectively). Then, the
secondary C7 hydroxy group of alcohol 17 was eliminated to generate the TBSꢀprotected
lentiginosine 19 through the Barton–McCombie radical deoxygenation method30 involving
esterification of 17 with thionocarbonylꢀ1,1′ꢀdiimidazole (TCDI, 2.0 equiv) in refluxing THF,
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 36
1
2
3
4
5
6
7
8
9
followed by radical reduction of the resulting thiocarbonylimidazolide intermediate 18 with
tributyltinhydride (4.0 equiv) in the presence of 2,2′ꢀazobisisobutyronitrile (AIBN). Alternatively, 19
could be easily acquired in 55% yield from 7ꢀindolizidinone 16 upon reduction with NaBH4 via its
tosylhydrazone (TsNHNH2, MeOH, reflux, 3 h, then NaBH4).31 Final hydrolysis of 19 with 3 N
hydrochloric acid (HCl) in aqueous acetonitrile at room temperature, followed by neutralization of the
resulting hydrochloride salt with ionꢀexchange resin (Dowex OH– form), furnished an 80% yield of
free base (+)ꢀ1 as a white solid. The 1H and 13C NMR spectral data obtained from this material agreed
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
with those described for the natural substance (see the Supporting Information).28a In addition, the
20
optical rotation of the synthetic (+)ꢀ1 {[
previously reported {lit.28b
α]
D
= +3.1 (c 0.3, MeOH)} closely matched the value
]D = +1.7 (c 0.6, MeOH)}.
[α]
25 = +3.2 (c 0.27, MeOH); lit.32
[
α
D
Scheme 3. Synthesis of (+)ꢀ/(–)ꢀLentiginosines ((+)/(–)ꢀ1)
OTBS
OTBS
OTBS
OTBS
H
N
H
H
HO
O
O
H2 (balloon)
Pd/C, EtOAc
OTBS
OTBS
N
N
4a
16 (15%)
17 (68%)
TsNHNH2, MeOH;
then NaBH4
TCDI, THF,
reflux, 6h
55%
88%
OTBS
H
OTBS
H
3N HCl;
CH3CN
nꢀBu3SnH
AIBN
Im
O
OTBS
OTBS
(+)ꢀ1
PhMe, reflux
S
rt, 3h, 80%
N
N
75%
19
18
Im = imidazole
H2
ent-4a
ent-16 (15%)
ent-17 (67%)
Pd/C
TCDI, THF
85%
nꢀBu3SnH,
AIBN
3N HCl,
CH3CN
ent-18
ent-19
(ꢀ)ꢀ1
75%
81%
Next, the same synthetic sequence was successfully applied to entꢀ4a to prepare (–)ꢀ1 with
comparable overall yield (cf. Scheme 3). The product obtained was spectroscopically identical to the
12
ACS Paragon Plus Environment

Page 13 of 36
The Journal of Organic Chemistry
1
2
3
4
20
literature data reported for (–)ꢀlentiginosine. The optical rotation of (–)ꢀ1 {[
α]
= –1.8 (c 0.32,
D
5
6
7
MeOH); lit.28b 23 = –1.6 (c 0.24, MeOH)} was opposite to that of the (+)ꢀlentiginosine.
[α]
D
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This promising azaꢀDiels–Alder reaction strategy could also be effectively expanded to the
preparation of structural analogue of relevant indolizidine iminosugars. (–)ꢀSteviamine was recently
isolated from Stevia rebaudiana (Asteraceae) leaves and represents
a new type of
polyhydroxyindolizidines with a methyl group at C5 position.33a Yu’s group first synthesized the
enantiomer and its C5 epimer of this iminosugar employing nucleophilic addition of organometallic
reagents to a Dꢀriboseꢀderived cyclic nitrone followed by intramolecular reductive amination or SN2
displacement as key steps to form the indolizidine framework.33b Furthermore, (–)ꢀsteviamine was
disclosed by them as the first natural molecule that possesses a weak inhibitory activity against
α
ꢀgalactosaminidase (GalNAcase).33b With the aim of studying the structureꢀactivity relationship and
searching for possible antiꢀGalNAcase candidate with improved bioactivity, we now report on the
synthesis of (–)ꢀ2ꢀepiꢀsteviamine (23), a C2 epimer of (–)ꢀsteviamine, by exploiting 5ꢀmethyl
indolizidinone 4g as key precursor (Scheme 4). The synthesis began with a fully diastereoselective
hydrogenolysis of 4g, which cleanly delivered saturated 20 as a sole isomer in 75% yield. The
absolute stereochemistries of the newly formed asymmetric C5 and C7 of 20 were determined to be R
and S, respectively (characteristic NOE correlations: H7–H8a, H5–H9, and H5–H7). Product 20
derives from the preferred equatorial attack of the hydrogen on 4g.34 Again, by means of the same
twoꢀstep deoxygenation protocol, 20 was transformed via 21 into the corresponding deoxygenated 22,
which was catalytically hydrogenated in acidic medium (H2, 10% Pd/C, 6 N HCl, MeOH, 50 °C, 20
h) to yield triol 23 as a white solid in a good 85% yield from 22 after ionꢀexchange chromatography
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 36
1
2
3
4
5
6
(OH– form). The structure of the final product was unambiguously confirmed on the basis of 1D and
2D NMR, as well as highꢀresolution ESIꢀTOF MS spectral analysis.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Synthesis of (–)ꢀ2ꢀepiꢀSteviamine (23)
OBn
OBn
OBn
OBn
OBn
H
H
O
HO
H2 (balloon)
N
N
Pd/C, EtOAc
OBn
75%
4g
20
TCDI, THF,
reflux, 6h
86%
OR
H
N
OBn
OBn
nꢀBu3SnH, AIBN
PhMe, reflux
H
N
Im
O
OR
OR
S
75%
OBn
21
22, R = Bn
H2 (30atm), Pd/C
6N HCl; MeOH
85%
2ꢀepi-Steviamine (23), R = H
CONCLUSION
In conclusion, we have developed an Yb (III)ꢀmediated [4+2] cycloaddition reaction between
Danishefskyꢀtype dienes and a broad spectrum of chiral, unactivated, fiveꢀmembered cyclic aldimines
with complete regioselectivity and high degree of diastereoselectivity. The stereoselectivity of the
cycloaddition is generally controlled by the C3 stereocenter of the imine heterodienophile. This
methodology opens a convergent and ready access to stereochemically rich indolizidine enaminones
that are extremely useful synthons for transformation into diverse arrays of polyhydroxyindolizidine
iminosugars. Starting from the obtained indolizidinones 4a/entꢀ4a, and 4g, concise syntheses of
(+)ꢀ/(–)ꢀlentiginosines (1) and nonꢀnatural (–)ꢀ2ꢀepiꢀsteviamine (23) have been accomplished in four
steps with overall yields of 36%, 35%, and 41%, respectively. Research is now underway to prepare
more complex indolizidine glycosidase inhibitors.
14
ACS Paragon Plus Environment

Page 15 of 36
The Journal of Organic Chemistry
1
2
3
4
EXPERIMENTAL SECTION
5
6
7
8
9
(3S,4S)ꢀNꢀChloroꢀ3,4ꢀbis(benzyloxy)pyrrolidine (8b). To a solution of 7b (285 mg, 1.01 mmol)
in dry Et2O (10 mL) was added NCS (135 mg, 1.01 mmol), the mixture was stirred under N2 at room
temperature for 30 min. The reaction mixture was diluted with Et2O (10 mL) and washed with water
(20 mL). The aqueous layer was extracted with Et2O (20 mL × 2) and the combined organic layer was
washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under
reduced pressure to give a residue, which was purified by silica gel column chromatography (30:1,
petroleum ether–EtOAc) to afford compound 8b as a colorless oil (289 mg, 90%). Rf 0.50 (20:1,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
1
petroleum ether–EtOAc). [α]D +30.5 (c 1.3, CHCl3); H NMR (400 MHz, CDCl3):
10H), 4.52 (d, 2H, J = 12.4 Hz), 4.48 (d, 2H, J = 12.4 Hz), 4.09 (t, 2H, 4.8 Hz), 3.52 (dd, 2H, J = 6.4,
10 Hz), 3.23 (dd, 2H, J = 3.6, 10 Hz); 13C NMR (100 MHz, CDCl3):
66.2, 71.6, 82.4, 127.7, 127.8,
δ 7.37–7.31 (m,
δ
128.4, 137.4; IR (KBr) 3064, 3029, 2969, 2889, 1455 cm–1; HRMS (ESIꢀTOF) calcd for C18H20ClNO2
[M+H]+ 318.1261, found 318.1258.
(3S,4S)ꢀ3,4ꢀBis(benzoyloxy)pyrroline trimer (6b′). To a solution of 8b (280 mg, 0.88 mmol) in
dry Et2O (18 mL) was added DBU (0.53 mL, 3.52 mmol). The reaction mixture was stirred under N2
at room temperature for 4 h. The reaction was diluted with Et2O, and the mixture was washed with
water and brine. The organic layer was separated, dried over anhydrous Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel
column chromatography (7:1, petroleum ether–EtOAc) to afford compound 6b′ as a colorless oil (193
mg, 78%). Rf 0.45 (4:1, petroleum ether–EtOAc). [α]D20 +16.7 (c 0.85, CHCl3); 1H NMR (400 MHz,
CDCl3):
δ 7.36–7.27 (m, 30H), 4.56 (s, 6H), 4.51 (d, 3H, J = 12.0 Hz), 4.42 (d, 3H, J = 12.0 Hz),
4.01–3.98 (m, 3H), 3.90 (dd, 3H, J = 3.2, 4.8 Hz), 3.09–3.05 (m, 6H), 2.64 (dd, 3H, J = 6.8, 9.6 Hz);
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 36
1
2
3
4
13C NMR (100 MHz, CDCl3):
δ 50.4, 71.2, 71.6, 82.1, 84.2, 85.3, 127.6, 127.7, 127.9, 128.28, 128.3,
5
6
7
8
137.9, 138.0; IR (KBr) 3062, 3030, 2921, 2860, 1454 cm–1; HRMS (ESIꢀTOF) calcd for C54H57N3O6
[M+Na]+ 866.4145, found 866.4138.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3S,4S)ꢀNꢀChloroꢀ3,4ꢀbis(methoxymethoxy)pyrrolidine (8c). Prepared from 7c (300 mg, 1.57
mmol) and NCS (210 mg, 1.57 mmol) in dry Et2O (15 mL) following the procedure similar to that for
7b → 8b. The residue was purified by silica gel column chromatography (6:1, petroleum
ether–EtOAc) to afford compound 8c as a colorless oil (311 mg, 88%). Rf 0.30 (5:1, petroleum
20
1
ether–EtOAc). [α]D –1.3 (c 1.2, CHCl3); H NMR (400 MHz, CDCl3):
4.65 (d, 2H, J = 6.8 Hz), 4.20–4.17 (m, 2H), 3.55 (dd, 2H, J = 6, 10.4 Hz), 3.38 (s, 6H), 3.19 (dd, 2H,
J = 4.4, 10.4 Hz); 13C NMR (100 MHz, CDCl3):
55.5, 66.5, 80.7, 95.8; IR (KBr) 2944, 2893, 1470,
δ 4.71 (d, 2H, J = 7.2 Hz),
δ
1152, 1111, 1039 cm–1; HRMS (ESIꢀTOF) calcd for C8H16ClNO4 [M+H]+ 226.0846, found 226.0845.
(3S,4S)ꢀ3,4ꢀBis(methoxymethoxy)pyrroline trimer (6c′). Prepared from 8c (300 mg, 1.33 mmol)
and DBU (0.80 mL, 5.32 mmol) in dry Et2O (26 mL) following the procedure similar to that for 8b →
6b′. The residue was purified by silica gel column chromatography (3:1, petroleum ether–EtOAc) to
20
afford compound 6c′ as a colorless oil (188 mg, 75%). Rf 0.40 (1:1, petroleum ether–EtOAc). [α]D
1
+35.3 (c 1.4, CHCl3); H NMR (400 MHz, CDCl3):
δ 4.75 (d, 3H, J = 7.2 Hz), 4.71 (d, 6H, J = 6.8
Hz), 4.65 (d, 3H, J = 6.8 Hz), 4.10–4.05 (m, 6H), 3.40 (s, 9H), 3.38 (s, 9H), 3.15 (dd, 3H, J = 3.2,
10.0 Hz), 3.03 (d, 3H, J = 5.2 Hz), 2.81 (dd, 3H, J = 6.4, 9.6 Hz); 13C NMR (100 MHz, CDCl3):
δ
51.2, 55.4, 55.5, 79.9, 83.0, 84.5, 95.5, 95.6; IR (KBr) 2942, 2893, 1466, 1152, 1039 cm–1; HRMS
(ESIꢀTOF) calcd for C24H45N3O12 [M+Na]+ 590.2901, found 590.2905.
(S)ꢀNꢀBenzylꢀ3ꢀtertꢀbutoxycarbonyloxypyrrolidine (10). To a solution of 9 (1.00 g, 5.65 mmol)
in dry THF (20 mL) were added a catalytic amount of Bu2SnO (141 mg, 0.56 mmol), K2CO3 (1.46 g,
16
ACS Paragon Plus Environment

Page 17 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
11.3 mmol), and Boc2O (2.46 g, 11.3 mmol) at room temperature. The mixture was stirred at 30 °C
for 24 h. Then the mixture was poured into water and extracted with ethyl acetate (30 mL × 3). The
combined organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel
column chromatography (3:1, petroleum ether–EtOAc) to afford compound 10 as a colorless oil (1.14
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
1
g, 73%). Rf 0.50 (2:1, petroleum ether–EtOAc). [α]D –5.1 (c 1.7, CHCl3); H NMR (400 MHz,
CDCl3): 7.31–7.28 (m, 4H), 7.25–7.23 (m, 1H), 5.06–5.02 (m, 1H), 3.65 (d, 1H, J = 12.8 Hz), 3.59
δ
(d, 1H, J = 12.8 Hz), 2.88 (dd, 1H, J = 4.8, 10.8 Hz), 2.71 (dd, 1H, J = 7.2, 16.0 Hz), 2.64 (dd, 1H, J =
4.2, 10.8 Hz), 2.49 (dd, 1H, J = 8.0, 14.4 Hz), 2.29–2.20 (m, 1H), 1.93–1.86 (m, 1H), 1.47 (s, 9H);13C
NMR (100 MHz, CDCl3):
δ 27.7, 31.8, 52.4, 59.6, 60.0, 76.5, 81.9, 126.9, 128.2, 128.7, 138.5, 153.2;
IR (KBr) 3062, 3028, 2978, 2793, 1737, 1454 cm–1; HRMS (ESIꢀTOF) calcd for C16H23NO3 [M+H]+
278.1756, found 278.1759.
(S)ꢀNꢀChloroꢀ3ꢀtertꢀbutoxycarbonyloxypyrrolidine (11). To a solution of 10 (1.00 g, 3.61 mmol)
in CH3OH (15 mL) was added 10% Pd/C (200 mg). The suspension was stirred under a hydrogen
atmosphere at room temperature for 4 h, then the insoluble material was filtered off, the filtrate was
concentrated under reduced pressure to give a residue which was extracted with Et2O. The organic
extract was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under
reduced pressure to dryness. The residue was directly used for the next step without further
purification. NCS (482 mg, 3.61 mmol) was added to a solution of obtained residue in dry Et2O (30
mL). The mixture was stirred under N2 at room temperature for 30 min, then was diluted with Et2O
(30 mL). The resulting mixture was washed with water and brine, dried over anhydrous Na2SO4, and
filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 36
1
2
3
4
5
6
silica gel column chromatography (20:1, petroleum ether–EtOAc) to afford compound 11 as a
colorless oil (479 mg, 60% over two steps). Rf 0.50 (10:1, petroleum ether–EtOAc). [α]D20 –2.1 (c 1.0,
7
8
9
CHCl3); 1H NMR (400 MHz, CDCl3):
(m, 1H), 3.30 (dd, 1H, J = 3.2, 12.4 Hz), 3.18–3.12 (m, 1H), 2.47–2.37 (m, 1H), 2.06–1.98 (m, 1H),
1.49 (s, 9H); 13C NMR (100 MHz, CDCl3):
27.6, 30.9, 60.9, 67.7, 75.1, 82.3, 152.8; IR (KBr) 2981,
δ 5.16–5.11 (m, 1H), 3.53 (dd, 1H, J = 6.4, 12.4 Hz), 3.40–3.34
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δ
2852, 1740, 1457 cm–1; HRMS (ESIꢀTOF) calcd for C9H16ClNO3 [M+H]+ 222.0897, found 222.0900.
(S)ꢀ3ꢀtertꢀButoxycarbonyloxypyrroline trimer (6d′). Prepared from 11 (400 mg, 1.80 mmol) and
DBU (1.08 mL, 7.20 mmol) in dry Et2O (36 mL) following the procedure similar to that for 8b → 6b′.
The residue was purified by silica gel column chromatography (10:1, petroleum ether–EtOAc) to
20
afford compound 6d′ as a colorless oil (233 mg, 70%). Rf 0.50 (4:1, petroleum ether–EtOAc). [α]D
–3.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
(dt, 3H, J = 3.6, 8.4 Hz), 2.65 (dd, 3H, J = 8.4, 16.0 Hz), 2.44–2.34 (m, 3H), 1.79–1.71 (m, 3H), 1.48
(s, 27H); 13C NMR (100 MHz, CDCl3):
27.7, 28.9, 44.5, 76.8, 82.3, 84.8, 153.0; IR (KBr) 2978,
δ 4.93–4.90 (m, 3H), 3.21(d, 3H, J = 4.8 Hz), 3.05
δ
2928, 2853, 1739, 1457 cm–1; HRMS (ESIꢀTOF) calcd for C27H45N3O9 [M+Na]+ 578.3053, found
578.3048.
(3R,4R)ꢀNꢀBenzylꢀ3ꢀtertꢀbutoxycarbonyloxyꢀ4ꢀhydroxypyrrolidine (13). Prepared from 12 (1.00
g, 5.21 mmol), Bu2SnO (130 mg, 0.52 mmol), K2CO3 (1.44 g, 10.4 mmol), and Boc2O (1.36 g, 6.25
mmol) in dry THF (20 mL) following the procedure similar to that for 9 → 10. The residue was
purified by silica gel column chromatography (40:1, CH2Cl2–MeOH) to afford compound 13 as a
20
1
colorless oil (1.24 g, 81%). Rf 0.50 (12:1, CH2Cl2–MeOH). [α]D +18.5 (c 1.2, CHCl3); H NMR
(400 MHz, CDCl3): 7.31–7.25 (m, 5H), 4.68–4.71 (m, 1H), 4.25–4.22 (m, 1H), 3.67 (d, 1H, J = 12.8
δ
Hz), 3.55 (d, 1H, J = 12.8 Hz), 3.00–2.94 (m, 2H), 2.65 (dd, 1H, J = 4.0, 10.8 Hz), 2.52 (dd, 1H, J =
18
ACS Paragon Plus Environment

Page 19 of 36
The Journal of Organic Chemistry
1
2
3
4
5.6, 9.6 Hz), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3):
δ
27.7, 57.5, 59.66, 59.7, 76.8, 82.8, 84.0,
5
6
7
8
127.1, 128.2, 128.8, 137.8, 153.9; IR (KBr) 3414, 3063, 3029, 2978, 2933, 2800, 1739, 1454 cm–1;
HRMS (ESIꢀTOF) calcd for C16H23NO4 [M+Na]+ 316.1525, found 316.1532.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3R,4R)ꢀNꢀBenzylꢀ3ꢀtertꢀbutyldimethylsilyloxyꢀ4ꢀtertꢀbutoxycarbonyloxypyrrolidine (14). To a
solution of 13 (1.00 g, 3.41 mmol) in dry DMF (10 mL) were added imidazole (469 mg, 6.82 mmol)
and TBDMSCl (614 mg, 4.09 mmol) at 0 °C. The reaction mixture was warmed gradually to room
temperature and stirred for 3 h at the same temperature. The resulting mixture was added to water (20
mL), extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous
Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which
was purified by silica gel column chromatography (40:1, petroleum ether–EtOAc) to afford
compound 14 as a colorless oil (1.18 g, 85%). Rf 0.50 (20:1, petroleum ether–EtOAc). [α]D20 –30.5 (c
1
1.6, CHCl3); H NMR (400 MHz, CDCl3):
δ 7.31–7.28 (m, 4H), 7.26–7.23 (m, 1H), 4.85–4.83 (m,
1H), 4.31 (dt, 1H, J = 2.4, 6.0 Hz), 3.66 (d, 1H, J = 13.2 Hz), 3.55 (d, 1H, J = 13.2 Hz), 3.06 (dd, 1H,
J = 6.4, 9.6 Hz), 2.86 (dd, 1H, J = 6.4, 10.8 Hz), 2.74 (dd, 1H, J = 2.4, 10.8 Hz), 2.30 (dd, 1H, J = 5.6,
9.6 Hz), 1.47 (s, 9H), 0.87 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ –5.0,
–4.9, 18.0, 25.7, 27.7, 58.1, 60.1, 60.9, 76.7, 82.0, 83.5, 127.0, 128.2, 128.7, 138.3, 153.1; IR (KBr)
3063, 3029, 2955, 2931, 2857, 1741, 1469 cm–1; HRMS (ESIꢀTOF) calcd for C22H37NO4Si [M+H]+
408.2570, found 408.2567.
(3R,4R)ꢀNꢀChloroꢀ3ꢀtertꢀbutyldimethylsilyloxyꢀ4ꢀtertꢀbutoxycarbonyloxypyrrolidine
(15).
Prepared from 14 (1.16 g, 2.85 mmol) following the procedure similar to that for 10 → 11. The
residue was purified by silica gel column chromatography (60:1, petroleum ether–EtOAc) to afford
compound 15 as a colorless oil (652 mg, 65% over two steps). Rf 0.50 (40:1, petroleum ether–EtOAc).
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 36
1
2
3
4
20
1
[α]D –34.9 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3):
δ 4.86–4.83 (m, 1H), 4.36–4.32 (m, 1H),
5
6
7
8
9
3.60 (dd, 1H, J = 6.4, 10.4 Hz), 3.56 (dd, 1H, J = 6.0, 12.0 Hz), 3.30 (dd, 1H, J = 2.4, 12.0 Hz), 2.99
(dd, 1H, J = 5.2, 10.4 Hz), 1.48 (s, 9H), 0.88 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CDCl3):
1744, 1470 cm–1; HRMS (ESIꢀTOF) calcd for C15H30ClNO4Si [M+Na]+ 374.1530, found 374.1559.
(3R,4R)ꢀ3ꢀtertꢀButoxycarbonyloxyꢀ4ꢀ(tertꢀbutyldimethylsilyloxy)pyrroline trimer (6f′).
δ –5.1, –5.0, 17.9, 25.6, 27.7, 66.3, 68.7, 75.7, 82.4, 82.7, 152.7; IR (KBr) 2956, 2932, 2857,
Prepared from 15 (400 mg, 1.14 mmol) and DBU (0.68 mL, 4.56 mmol) in dry Et2O (23 mL)
following the procedure similar to that for 8b → 6b′. The residue was purified by silica gel column
chromatography (20:1, petroleum ether–EtOAc) to afford compound 6f′ as a colorless oil (258 mg,
20
1
72%). Rf 0.50 (15:1, petroleum ether–EtOAc). [α]D –31.3 (c 1.2, CHCl3); H NMR (400 MHz,
CDCl3): 4.91–4.89 (m, 3H), 4.23–4.21 (m, 3H), 3.11–3.05 (m, 6H), 2.89–2.85 (m, 3H), 1.48 (s,
27H), 0.88 (s, 27H), 0.09–0.03 (m, 18H); 13C NMR (100 MHz, CDCl3):
–5.0, 18.0, 25.7, 27.7, 53.7,
δ
δ
75.1, 82.3, 83.0, 84.2, 152.6; IR (KBr) 2956, 2890, 2857, 1745, 1467 cm–1; HRMS (ESIꢀTOF) calcd
for C45H87N3O12Si3 [M+Na]+ 968.5495, found 968.5487.
General Procedure for AzaꢀDielsꢀAlder Reaction of Cyclic Imines with DanishefskyꢀType
Dienes. To a suspension of Yb(OTf)3 (0.075 mmol) in dry CH2Cl2 (1 mL) was added a solution of
imine monomer (0.15 mmol) or imine trimer (0.05 mmol) in dry CH2Cl2 (1 mL) at –40 °C under N2.
The mixture was stirred for 10 min at the same temperature, then a solution of Danishefskyꢀtype diene
(0.45 mmol) in dry CH2Cl2 (1 mL) was added dropwise. After being stirred for 2.5 h at the same
temperature, the mixture was warmed gradually to 0 °C within 30 min. The solution was quenched
with saturated NaHCO3, diluted with CH2Cl2, and then the resulting mixture was washed with water
and brine. The organic layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate
20
ACS Paragon Plus Environment

Page 21 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
was concentrated under reduced pressure to give a residue, which was purified by silica gel column
chromatography to give the corresponding cycloadducts.
7
8
9
Compounds 4a and 4a′. 4a: colorless oil (73% yield, 11:1 dr); Rf 0.53 (1:1, petroleum
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ether–EtOAc). [α]D20 +300.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
δ 7.07 (d, 1H, J = 7.2 Hz),
4.93 (d, 1H, J = 7.2 Hz), 4.11 (dd, 1H, J = 4.8, 13.6 Hz), 3.91 (t, 1H, J = 4.8 Hz), 3.73 (dd, 1H, J = 5.6,
10.4 Hz), 3.64 (dt, 1H, J = 5.6, 16.4 Hz), 3.26 (dd, 1H, J = 4.4, 10.4 Hz), 2.54 (t, 1H, J = 16.0 Hz),
2.43 (dd, 1H, J = 5.6, 16.0 Hz), 0.89 (s, 9H), 0.88 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07
(s, 3H); 13C NMR (100 MHz, CDCl3):
δ –4.8, –4.7, –4.6, –4.3, 17.8, 17.81, 25.6, 25.7, 39.1, 55.5,
63.1, 77.2, 82.3, 97.5, 150.3, 191.7; IR (KBr) 2955, 2931, 2889, 2857, 1640, 1588, 1465 cm–1; HRMS
(ESIꢀTOF) calcd for C20H39NO3Si2 [M+H]+ 398.2547, found 398.2539. 4a′: colorless oil (6% yield);
20
1
Rf 0.55 (1:1, petroleum ether–EtOAc). [α]D –215.3 (c 0.76, CHCl3); H NMR (400 MHz, CDCl3):
δ
7.18 (d, 1H, J = 7.2 Hz), 4.94 (d, 1H, J = 7.2 Hz), 4.11–4.09 (m, 1H), 4.04 (d, 1H, J = 16.4 Hz),
3.96–3.94 (m, 1H), 3.73 (dd, 1H, J = 4.8, 10.8 Hz), 3.25 (d, 1H, J = 10.8 Hz), 2.72 (t, 1H, J = 16.4
Hz), 2.13 (dd, 1H, J = 5.2, 16.0 Hz), 0.89 (s, 9H), 0.88 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H),
0.07 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ –4.9, –4.8, –4.6, –4.7, 17.8, 17.9, 25.6, 25.7, 35.2, 56.0,
59.5, 75.8, 77.6, 96.3, 150.2, 192.6; IR (KBr) 2954, 2927, 1642, 1586, 1461 cm–1; HRMS (ESIꢀTOF)
calcd for C20H39NO3Si2 [M+H]+ 398.2547, found 398.2546.
20
Compound 4b. Colorless oil (65% yield, 10:1 dr); Rf 0.40 (85:1, CH2Cl2–CH3OH); [α]D +136.4
(c 1.4, CHCl3); 1H NMR (400 MHz, CDCl3):
δ 7.39–7.30 (m, 10H), 7.04 (d, 1H, J = 7.2 Hz), 4.96 (d,
1H, J = 7.2 Hz), 4.63 (s, 2H), 4.60 (d, 1H, J = 11.6 Hz), 4.55 (d, 1H, J = 12.0 Hz), 4.17–4.13 (m, 1H),
3.97–3.95 (m, 1H), 3.82–3.75 (m, 1H), 3.69 (dd, 1H, J = 2.0, 11.2 Hz), 3.46 (dd, 1H, J =3.6, 11.2 Hz),
2.53 (d, 1H, J = 1.2 Hz), 2.51 (s, 1H); 13C NMR (100 MHz, CDCl3):
δ 39.9, 53.4, 61.7, 72.1, 72.4,
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 36
1
2
3
4
5
6
7
8
9
82.0, 87.0, 98.3, 127.7, 128.1, 128.6, 137.2, 150.1, 191.5; IR (KBr) 3057, 3032, 2966, 2922, 2851,
1638, 1576, 1467 cm–1; HRMS (ESIꢀTOF) calcd for C22H23NO3 [M+H]+ 350.1756, found 350.1759.
Compound 4c. Colorless oil (62% yield, 5:1 dr); Rf 0.45 (1:1, acetone–cyclohexane); [α]D20 +291.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3):
δ 7.08 (d, 1H, J = 7.2 Hz), 4.98 (d, 1H, J = 7.2 Hz), 4.79
(d, 1H, J = 7.2 Hz), 4.74 (d, 1H, J = 6.8 Hz), 4.67 (dd, 2H, J = 2.8, 6.8 Hz), 4.20 (dd, 1H, J = 4.8, 11.2
Hz), 4.06–4.03 (m, 1H), 3.80 (dd, 1H, J = 6.8, 11.2 Hz), 3.74–3.70 (m, 1H), 3.46 (dd, 1H, J = 5.2,
11.2 Hz), 3.39 (s, 3H), 3.38 (s, 3H), 2.62–2.51 (m, 2H); 13C NMR (100 MHz, CDCl3):
δ 39.5, 53.4,
55.7, 55.8, 60.9, 80.4, 85.1, 96.3, 96.5, 98.3, 150.0, 191.7; IR (KBr) 2946, 2894, 2826, 1636, 1581,
1460, 1152, 1106, 1039 cm–1; HRMS (ESIꢀTOF) calcd for C12H19NO5 [M+Na]+ 280.1161, found
280.1201.
Compound 4d. Pale yellow oil (73% yield, >99:1 dr); Rf 0.35 (1:3, petroleum ether–EtOAc);
[α]D20 –263.7 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
δ 7.08 (d, 1H, J = 6.8 Hz), 4.94–4.87 (m,
2H), 3.75 (dt, 1H, J = 5.2, 16.4 Hz), 3.64–3.58 (m, 1H), 3.53–3.48 (m, 1H), 2.59 (dd, 1H, J = 5.2,
16.0 Hz), 2.49–2.42 (m, 1H), 2.41 (t, 1H, J = 16.4 Hz), 2.09–2.00 (m, 1H), 1.46 (s, 9H); 13C NMR
(100 MHz, CDCl3):
δ 27.6, 30.8, 39.3, 47.6, 62.3, 79.5, 83.1, 98.2, 149.8, 152.6, 191.2; IR (KBr)
2959, 2927, 2855, 1740, 1630, 1577, 1459 cm–1; HRMS (ESIꢀTOF) calcd for C13H19NO4 [M+Na]+
276.1212, found 276.1207.
20
Compound entꢀ4a. Colorless oil (71% yield, 10:1 dr); [α]D –295.3 (c 1.0, CHCl3); its
spectroscopic data were identical with those of 4a.
20
Compound 4e. Yellow oil (63% yield, >99:1 dr); Rf 0.45 (2:3, petroleum ether–EtOAc); [α]D
–139.6 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
δ 7.36–7.19 (m, 15H), 7.20 (d, 1H, J = 7.2 Hz),
4.95 (d, 1H, J = 7.6 Hz), 4.61 (d, 4H, J = 3.2 Hz), 4.49 (s, 2H), 3.96 (d, 2H, J = 5.2 Hz), 3.90 (dd, 1H,
22
ACS Paragon Plus Environment

Page 23 of 36
The Journal of Organic Chemistry
1
2
3
4
J = 7.2, 14,4 Hz), 3.80 (d, 1H, J = 3.2 Hz), 3.56–3.46 (m, 2H), 2.55 (s, 1H), 2.52 (d, 1H, J = 8.0 Hz);
5
6
7
13C NMR (100 MHz, CDCl3):
δ 40.5, 61.3, 64.5, 69.2, 72.3, 72.5, 73.4, 84.2, 87.9, 98.1, 127.7, 127.71,
8
9
127.8, 128.0, 128.07, 128.1, 128.5, 128.52, 128.53, 128.56, 137.1, 137.3, 149.9, 191.3; IR (KBr) 3061,
3031, 2923, 2861, 1638, 1576, 1455 cm–1; HRMS (ESIꢀTOF) calcd for C30H31NO4 [M+H]+ 470.2331,
found 470.2334.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 4f. Yellow oil (70% yield, 11:1 dr); Rf 0.50 (1:3, acetone–cyclohexane). [α]D20 +261.1
1
(c 1.5, CHCl3); H NMR (400 MHz, CDCl3):
δ 4.91 (s, 1H), 4.13–4.10 (m, 1H), 3.92 (t, 1H, J = 5.2
Hz), 3.71 (dd, 1H, J = 6.4, 10.8 Hz), 3.62 (dt, 1H, J = 14.4, 6.0 Hz), 3.28 (dd, 1H, J = 5.2, 10.8 Hz),
2.50–2.40 (m, 2H), 1.98 (s, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H),
0.08 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ –4.7, –4.66, –4.5, –4.3, 17.8, 19.9, 25.66 , 25.7, 39.1,
52.5, 63.8, 76.4, 81.8, 98.5, 160.5, 191.0; IR (KBr) 2957, 2930, 2892, 2858, 1619, 1543, 1471 cm–1;
HRMS: calcd for C21H41NO3Si2 [M+H]+, 412.2703, found 412.2699.
20
Compound 4g. Yellow oil (65% yield, >99:1 dr); Rf 0.40 (2:3, petroleum ether–EtOAc); [α]D
+138.8 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3):
δ 7.37–7.28 (m, 10H), 7.24–7.21 (m, 5H), 4.90
(s, 1H), 4.56 (d, 2H, J = 12.0 Hz), 4.49 (s, 2H), 4.45 (s, 2H), 4.08–4.05 (m, 2H), 3.95 (dt, 1H, J = 4.0,
16.0 Hz), 3.84 (d, 1H, J = 3.2 Hz), 3.55 (d, 2H, J = 7.2 Hz), 2.53 (t, 1H, J = 16.0 Hz), 2.40 (dd, 1H, J
= 5.2, 16.0 Hz), 1.99 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 20.1, 39.8, 63.8 (2C), 68.2, 71.4, 71.6,
73.3, 84.2, 86.9, 99.4, 127.5, 127.6, 127.7, 127.9, 128.0, 128.4, 128.5, 137.0, 137.3, 137.4, 160.6,
190.7; IR (KBr) 3061, 3030, 2920, 2864, 1627, 1548, 1453 cm–1; HRMS (ESIꢀTOF) calcd for
C31H33NO4 [M+H]+ 484.2488, found 484.2494.
20
Compound 4h. Pale yellow oil (62% yield, 10:1 dr); Rf 0.40 (1:3, acetone–cyclohexane); [α]D
–296.2 (c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3):
δ 4.94 (s, 1H), 4.81 (t, 1H, J = 4.0 Hz), 4.36 (d,
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 36
1
2
3
4
5
6
1H, J = 4.8 Hz), 3.81 (td, 1H, J = 4.4, 16.0 Hz), 3.72 (dd, 1H, J = 5.6, 11.2 Hz), 3.41 (dd, 1H, J = 3.2,
11.2 Hz), 2.61 (t, 1H, J = 16.0 Hz), 2.49 (dd, 1H, J = 4.8, 16.0 Hz), 1.99 (s, 3H), 1.49 (s, 9H), 0.88 (s,
7
8
9
9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ –5.1, –4.9, 17.8, 20.1, 25.5, 27.6, 39.0,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
53.0, 62.2, 73.9, 83.3, 83.7, 99.2, 152.3, 160.3, 191.0; IR (KBr) 2959, 2913, 2857, 1745, 1637, 1563,
1472 cm–1; HRMS (ESIꢀTOF) calcd for C20H35NO5Si [M+H]+ 398.2363, found 398.2368.
(1S,2S,8aS)ꢀ1,2ꢀBis(tertꢀbutyldimethylsilyloxy)octahydroindolizinꢀ7ꢀone
(16)
and
(1S,2S,7R,8aS)ꢀl,2ꢀBis(tertꢀbutyldimethylsilyloxy)ꢀ7ꢀhydroxyoctahydroindolizine (17). To
a
solution of 4a (300 mg, 0.75 mmol) in EtOAc (10 mL) was added 10% Pd/C (90 mg). The suspension
was stirred under an atmosphere of H2 for 3 h at 35°C. The insoluble material was filtered off. The
filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel
column chromatography (1:6, acetone–cyclohexane) to afford compounds 16 (45 mg, 15%) and 17
(205 mg, 68%). Products 16 and 17 are known compounds and their spectroscopic data matched the
reported data.34
(1S,2S,7R,8aS)ꢀ7ꢀImidazolylthiocarbonyloxyꢀ1,2ꢀbis(tertꢀbutyldimethylsilyloxy)octahydroindo
lizine (18). To a solution of alcohol 17 (100 mg, 0.25 mmol) in dry THF (3 mL) was added
thionocarbonylꢀ1,1′ꢀdiimidazole (TCDI) (89 mg, 0.50 mmol). The mixture was heated at reflux
temperature for 6 h, and then cooled to room temperature and the solvent was evaporated. The
resulting residue was purified by silica gel column chromatography (1:5, acetone–cyclohexane) to
afford compound 18 as a yellow oil (113 mg, 88%). Rf 0.60 (1:2, acetone–cyclohexane). [α]D20 +25.7
(c 1.2, CHCl3); 1H NMR (400 MHz, CDCl3):
δ 8.33 (s, 1H), 7.62 (s, 1H), 7.03 (s, 1H), 5.42–5.37 (m,
1H), 4.05 (s, 1H), 3.80 (dd, 1H, J = 3.2, 8.0 Hz), 3.02 (d, 1H, J = 12.0 Hz), 2.86 (d, 1H, J = 10.0 Hz),
2.59 (t, 1H, J = 8.0 Hz), 2.43 (d, 1H, J = 10.4 Hz), 2.20–2.11 (m, 2H), 2.02 (t, 1H, J = 8.8 Hz),
24
ACS Paragon Plus Environment

Page 25 of 36
The Journal of Organic Chemistry
1
2
3
4
1.93–1.84 (m, 1H), 1.57 (dd, 1H, J = 11.2, 22.4 Hz), 0.89 (s, 9H), 0.88 (s, 9H), 0.08 (s, 3H), 0.07 (s,
5
6
7
3H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ –4.7, –4.3, –4.2, –4.1, 17.9, 25.8, 25.9,
8
9
29.5, 33.3, 49.7, 60.9, 66.5, 78.9, 81.3, 84.9, 117.8, 130.7, 136.8, 183.2. IR (KBr) 2954, 2930, 2857,
1466, 1248 cm–1; HRMS (ESIꢀTOF) calcd for C24H45N3O3SSi2 [M+H]+ 512.2798, found 512.2793.
(1S,2S,8aS)ꢀ1,2ꢀBis(tertꢀbutyldimethylsilyloxy)octahydroindolizine (19). Prepared from 18: To a
refluxing solution of tri-nꢀbutyltinhydride (0.21 mL, 0.76 mmol) in dry toluene (13 mL) was added a
mixture of 18 (100 mg, 0.19 mmol) and AIBN (5.4 mg, 0.03 mmol) in toluene (6 mL) by syringe
within 1 h. The mixture was heated under reflux for further 2 h. The solvent was evaporated and the
residue was purified by silica gel column chromatography (11:1, petroleum ether–EtOAc) to give 19
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
(55 mg, 75%) as a colorless oil. Rf 0.55 (5:1, petroleum ether–EtOAc). [α]D +17.1 (c 1.4, CHCl3);
1H NMR (400 MHz, CDCl3):
δ 3.98 (ddd, 1H, J = 2.0, 4.0, 8.0 Hz), 3.73 (dd, 1H, J = 4.0, 8.4 Hz),
2.92 (d, 1H, J = 10.8 Hz), 2.85 (dd, 1H, J = 2.0, 10.0 Hz), 2.53 (dd, 1H, J = 8.0, 10.0 Hz), 1.94–1.74
(m, 4H), 1.58–1.54 (m, 2H), 1.18–1.22 (m, 2H), 0.89 (s, 9H), 0.88 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H),
0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ –4.7, –4.3, –4.2, –4.1, 17.8, 17.9, 23.9,
24.8, 25.8, 25.9, 28.6, 53.3, 62.1, 68.4, 78.0, 85.1; IR (KBr) 2931, 2888, 2856, 1467, 1255 cm–1;
HRMS (ESIꢀTOF) calcd for C20H43NO2Si2 [M+H]+ 386.2911, found 386.2901.
Prepared from 16: To a solution of 16 (40 mg, 0.10 mmol) in dry MeOH (3 mL) were added
(pꢀtoluenesulfonyl)hydrazine (70 mg, 0.37 mmol) and freshly activated 4 Å molecular sieves. The
mixture was refluxed for 3 h (TLC monitoring). After cooling to 0 °C, a large excess of NaBH4 (93
mg, 2.45 mmol) was added and the mixture was heated under reflux for 3 h. The mixture was filtered
off, the filtrate was concentrated under reduced pressure to give a residue which was dissolved in
water and extracted with Et2O. The organic layer was separated, dried over anhydrous Na2SO4, and
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 36
1
2
3
4
5
6
7
8
9
filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by
silica gel column chromatography (11:1, petroleum ether–EtOAc) to give 19 (21 mg, 55%) as a
colorless oil.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1S,2S,8aS)ꢀ1,2ꢀDihydroxyoctahydroindolizine, (+)ꢀlentiginosine ((+)ꢀ1). To a solution of 19 (50
mg, 0.13 mmol) in CH3CN (1 mL) was added 3 N HCl (1 mL). The mixture was stirred at 25 °C for 3
h. Then, the mixture was neutralized by addition of anhydrous Na2CO3 at 0 °C. The mixture was
filtered and the obtained filtrate was concentrated under reduced pressure to dryness. The residue was
purified by silica gel column chromatography (5:1, CH2Cl2–CH3OH). The obtained compound was
purified by ionꢀexchange chromatography (Dowex OH– form) using distilled water to afford (+)ꢀ1 (16
mg, 80%) as a white solid. Rf 0.30 (5:1, CH2Cl2–CH3OH); mp: 106–108 °C (lit.28b 106–107 °C, lit.32
20
25
107–108 °C); [α]D +3.1 (c 0.30, CH3OH) {lit.28b [α]D +3.2 (c 0.27, CH3OH), lit.32 [α]D +1.7 (c
0.60, CH3OH)}; 1H NMR (400 MHz, D2O):
δ
4.08 (ddd, 1H, J = 2.0, 4.0, 7.6 Hz), 3.66 (dd, 1H, J =
4.0, 8.4 Hz), 2.96 (d, 1H, J = 11.2 Hz), 2.85 (d, 1H, J = 11.2 Hz), 2.66 (dd, 1H, J = 7.6, 11.2 Hz), 2.08
(dt, 1H, J = 2.8, 11.2 Hz), 1.99–1.90 (m, 2H), 1.83–1.79 (m, 1H), 1.63 (d, 1H, J = 13.2 Hz), 1.38–1.49
(m, 1H), 1.19–1.32 (m, 2H); 13C NMR (100 MHz, D2O):
85.5; HRMS (ESIꢀTOF) calcd for C8H15NO2 [M+Na]+ 180.1000, found 180.0982.
(1R,2R,8aR)ꢀ1,2ꢀDihydroxyoctahydroindolizine, ( )ꢀlentiginosine (( )ꢀ1). Using the same
fourꢀstep procedure as described for the preparation of (+)ꢀ1, ( )ꢀ1 was synthesized in 35% overall
yield (based on entꢀ4a) from entꢀ4a via intermediates entꢀ17, entꢀ18, and entꢀ19. Compound ( )ꢀ1: mp:
δ 25.7, 26.6, 30.2, 55.3, 62.9, 71.2, 78.2,
–
–
–
–
106–107 °C (lit.28b 106–107 °C, lit.32 106–107 °C); [α]D20 –1.8 (c 0.32, CH3OH) {lit.28b [α]D23 –1.6 (c
1
0.24, CH3OH), lit.32 [α]D –3.05 (c 1.0, CH3OH)}; Its H and 13C NMR spectroscopic data were
identical with those of (+)ꢀ1.
26
ACS Paragon Plus Environment

Page 27 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(1R,2R,3R,5R,7S,8aR)ꢀ1,2ꢀBis(benzyloxy)ꢀ3ꢀ(benzyloxymethyl)ꢀ5ꢀmethyloctahydroindolizinꢀ7ꢀ
ol (20). Prepared from 4g (200 mg, 0.41 mmol) and 10% Pd/C (60 mg) in EtOAc (6 mL) following
the procedure similar to that for 4a → 16 and 17. The residue was purified by silica gel column
chromatography (1:6, acetone–cyclohexane) to afford compound 20 as a pale yellow oil (150 mg,
75%). Rf 0.55 (1:3, acetone–cyclohexane). [α]D20 –20.8 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δ
7.32–7.21 (m, 15H), 4.65 (d, 1H, J = 12.0 Hz), 4.52 (d, 2H, J = 2.0 Hz), 4.43 (t, 3H, J = 12.0 Hz),
3.93 (d, 1H, J = 2.0 Hz), 3.70–3.64 (m, 2H), 3.57–3.51 (m, 2H), 3.43 (t, 1H, J = 8.4 Hz), 2.70 (t, 1H, J
= 8.0 Hz), 2.59–2.63 (m, 1H), 2.23 (d, 1H, J = 10.4 Hz), 1.84 (d, 1H, J =11.6 Hz), 1.23–1.17 (m, 3H),
1.14 (d, 3H, J = 6.0 Hz); 13C NMR (100 MHz, CDCl3):
δ 19.9, 39.6, 43.2, 49.2, 62.1, 62.3, 65.4, 68.7,
71.2, 71.7, 73.4, 85.7, 89.2, 127.5, 127.56, 127.6, 127.7, 128.2, 128.3, 128.33, 138.0, 138.2; IR (KBr)
3397, 3067, 3030, 2952, 2856, 1454 cm–1; HRMS (ESIꢀTOF) calcd for C31H37NO4 [M+H]+ 488.2801,
found 488.2798.
(1R,2R,3R,5R,7S,8aR)ꢀ7ꢀImidazolylthiocarbonyloxyꢀ1,2ꢀbis(benzyloxy)ꢀ3ꢀ(benzyloxymethyl)ꢀ5
ꢀmethyloctahydroindolizine (21). Prepared from 20 (150 mg, 0.31 mmol) and
thionocarbonylꢀ1,1′ꢀdiimidazole (TCDI) (110 mg, 0.62 mmol) in dry THF (3 mL) following the
procedure similar to that for 17 → 18. The residue was purified by silica gel column chromatography
(1:6, acetone–cyclohexane) to afford compound 21 as a yellow oil (159 mg, 86%). Rf 0.51 (1:4,
acetone–cyclohexane). [α]D20 –9.2 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3):
δ 8.31 (s, 1H), 7.59
(s, 1H), 7.59–7.21 (m, 15H), 7.02 (s, 1H), 5.38–5.40 (m, 1H), 4.66 (d, 1H, J = 12.6 Hz), 4.54 (dd, 2H,
J = 12.0, 13.2 Hz), 4.74–4.40 (m, 3H), 3.73 (d, 1H, J = 5.2 Hz), 3.67 (dd, 1H, J = 3.2, 8.8 Hz), 3.55
(dd, 1H, J = 3.6, 7.6 Hz), 3.47 (t, 1H, J = 8.0 Hz), 2.85 (t, 1H, J = 8.0 Hz), 2.78 (s, 1H), 2.48 (d, 1H, J
= 10.4 Hz), 2.15 (d, 1H, J = 11.6 Hz), 1.42–1.57 (m, 3H), 1.19 (d, 3H, J = 6.0 Hz); 13C NMR (100
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 36
1
2
3
4
MHz, CDCl3):
δ
19.9, 35.1, 38.2, 49.0, 61.9, 62.2, 65.5, 71.3, 71.8, 73.5, 80.6, 85.5, 89.1, 117.8,
5
6
7
8
9
127.6, 127.65, 127.7, 127.8, 128.2, 128.3, 128.33, 128.4, 130.6, 136.8, 137.87, 137.9, 138.0, 183.1; IR
(KBr) 3061, 3030, 2924, 2854, 1460, 1285 cm–1; HRMS (ESIꢀTOF) calcd for C35H39N3O4S [M+H]+
598.2740, found 598.2744.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1R,2R,3R,5R,8aR)ꢀ1,2ꢀBis(benzyloxy)ꢀ3ꢀ(benzyloxymethyl)ꢀ5ꢀmethyloctahydroindolizine (22).
Prepared from 21 (150 mg, 0.25 mmol), AIBN (7.1 mg, 0.04 mmol) and tri-nꢀbutyltinhydride (0.28
mL, 1.00 mmol) following the procedure similar to that for 18 → 19. The residue was purified by
silica gel column chromatography (6:1, petroleum ether–EtOAc) to afford compound 22 as a pale
yellow oil (88 mg, 75%). Rf 0.55 (3:1, petroleum ether–EtOAc). [α]D20 –32.9 (c 1.5, CHCl3); 1H NMR
(400 MHz, CDCl3):
δ 7.35–7.22 (m, 15H), 4.67 (d, 1H, J = 12.4 Hz), 4.53 (dd, 2H, J = 12.0, 16.4 Hz),
4.45 (d, 3H, J =12.8 Hz), 3.90 (d, 1H, J = 2.0 Hz), 3.72 (dd, 1H, J = 3.6, 8.4 Hz), 3.67 (d, 1H, J = 6.4
Hz), 3.57 (dd, 1H, J = 3.2, 11.2 Hz), 3.45 (t, 1H, J = 8.8 Hz), 2.58–2.53 (m, 2H), 1.95 (d, 1H, J = 7.6
Hz), 1.70 (s, 1H), 1.54 (d, 1H, J = 7.2 Hz), 1.18 (d, 3H, J = 2.4 Hz), 1.12 (d, 3H, J = 6.0 Hz); 13C
NMR (100 MHz, CDCl3):
δ 20.1, 24.0, 30.6, 34.1, 52.0, 62.7, 64.1, 65.1, 71.1, 71.7, 73.4, 85.2, 90.2,
127.4, 127.45, 127.5, 127.53, 127.7, 128.1, 128.2, 128.3, 138.2, 138.3, 138.4; IR (KBr) 3062, 3030,
2928, 2855, 1454 cm–1; HRMS (ESIꢀTOF) calcd for C31H37NO3 [M+H]+ 472.2852, found 472.2844.
(1R,2R,3R,5R,8aR)ꢀ3ꢀ(Hydroxymethyl)ꢀ5ꢀmethyloctahydroindolizineꢀ1,2ꢀdiol,
(–)ꢀ2ꢀepiꢀSteviamine (23). To a solution of 22 (46 mg, 0.10 mmol) in MeOH (2 mL) were added 10%
Pd/C (30 mg) and 6 N HCl (0.1 mL). The resulting suspension was stirred at 50 °C under 30 atm of
H2 for 20 h. The Pd/C was filtered off. After the solution was concentrated under reduced pressure, the
residue was dissolved in MeOH and neutralized with aqueous ammonium solution, concentrated
under reduced pressure. The residue was purified by ionꢀexchange chromatography (Dowex OH–
28
ACS Paragon Plus Environment

Page 29 of 36
The Journal of Organic Chemistry
1
2
3
4
form) using distilled water to afford 23 (17 mg, 85%) as a colorless oil. Rf 0.5 (3:1, CH2Cl2–CH3OH).
5
6
7
[α]D20 –15.1 (c 0.80, CH3OH); 1H NMR (400 MHz, D2O):
δ 4.08–4.07 (m, 1H), 3.97 (dd, 1H, J = 4.0,
8
9
11.6 Hz), 3.77 (dd, 1H, J = 8.0, 11.6 Hz), 3.70 (dd, 1H, J = 4.4, 8.4 Hz), 3.18 (d, 1H, J = 4.8 Hz),
2.74–2.72 (m, 1H), 2.70–2.65 (m, 1H), 1.96 (d, 1H, J = 14.4 Hz), 1.81–1.71 (m, 2H), 1.35–1.08 (m,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3H), 1.14 (d, 3H, J = 6.0 Hz); 13C NMR (100 MHz, D2O):
δ 21.0, 25.4, 30.8, 35.4, 54.2, 60.1, 67.4,
68.4, 81.6, 85.1; IR (KBr) 3390, 2926, 2831, 1451, 1381, 1118 cm–1; HRMS (ESIꢀTOF) calcd for
C10H19NO3 [M+Na]+, 224.1263, found 224.1264.
ACKNOWLEDGMENTS
We appreciate financial support from NSFC (21172156, 21021001), the National Basic Research
Program of China (973 Program, 2010CB833202), Ministry of Education (NCETꢀ08ꢀ0377,
20100181110082), and Sichuan Province (08ZQ026ꢀ029) of China.
*Supporting Information
1H and 13C NMR spectra for all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
REFERENCES
(1) For reviews, see: (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron:
Asymmetry 2000, 11, 1645–1680. (b) Watson, A. A.; Fleet, G. W. J. Asano, N.; Molyneux, R. J.; Nash,
R. J. Phytochemistry 2001, 56, 265–295.
(2) For selected reviews on the biological activity of iminosugars, see: (a) Asano, N. Glycobiology,
29
ACS Paragon Plus Environment