Radical cyclizations of acylsilanes in the synthesis of (+)-swainsonine and formal synthesis of (-)-epiquinamide

Article abstract of DOI:10.1016/j.tet.2010.12.048

Radical cyclization of acylsilane is an useful synthetic methodology. To demonstrate the versatility of this method using the cyclization as a key step, polyhydroxylated indolizidine (+)-swainsonine was synthesized through two different bond connection ap

Full text of DOI:10.1016/j.tet.2010.12.048

Tetrahedron 67 (2011) 1564e1574
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Radical cyclizations of acylsilanes in the synthesis of (þ)-swainsonine and formal
synthesis of (ꢀ)-epiquinamide
,
,
*
Ming-Jen Chen a b, Yeun-Min Tsai a
a Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, Republic of China
b Department of Applied Cosmetology and Graduate Institute of Cosmetic Science, Hungkuang University, Shalu, Taichung, Taiwan 433, Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Radical cyclization of acylsilane is an useful synthetic methodology. To demonstrate the versatility of this
method using the cyclization as a key step, polyhydroxylated indolizidine (þ)-swainsonine was syn-
thesized through two different bond connection approaches to construct the bicyclic skeleton. In the first
Received 4 November 2010
Received in revised form 14 December 2010
Accepted 15 December 2010
Available online 21 December 2010
approach, we used 2,3-isopropylidene-D-ribono-1,4-lactone (20) as a chiral building block to form the
indolizidine skeleton through a 1,6-cyclization. In the second approach, (S)-(þ)-5-oxo-2-tetrahydrofur-
ancarboxylic acid (23) was used to construct the same ring system through a 1,5-cyclization. Starting
from acid 23, we also synthesized exo-1-hydroxyquinolizidin-4-one (56), which was a synthetic
intermediate in the synthesis of polyhydroxylated quinolizidine (ꢀ)-epiquinamide.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Acylsilane
a
-Acylamino radical
Radical cyclization
(þ)-Swainsonine
(ꢀ)-Epiquinamide
Polyhydroxylated alkaloids
1. Introduction
Intramolecular free radical cyclization1 is an important syn-
thetic methodology for ring formation. Although intramolecular
free radical addition to a carbonyl group appears to be an useful
method for cyclic alcohol synthesis, this process is reversible and
favors the acyclic radical side (Scheme 1).2 Many methods3 were
developed to trap the cyclized alkoxy radical 2 to drive the reaction
toward cyclization. In our previous work, we devised a synthetic
equivalent of the formyl cyclization system 1 by replacing the for-
myl group with an acylsilane group4,5 as in radical 4. Cyclization of
O
O
H
HO
H
H
n
n
n
1
2
3
n = 1 or 2
Σ = SiR3
O
OΣ
O
Σ
ΣO
H
Σ
this radical affords a b-silyl substituted alkoxy radical intermediate
5. A key radical-Brook rearrangement6,7 occurs to generate a sily-
loxy substituted carbon radical 6. Due to the well-known strong
bonding between silicon and oxygen,8 the cyclization is essentially
propelled by this thermodynamic driving force. In the end, a silyl
group protected cyclic alcohol 7 can be obtained very efficiently.9
Polyhydroxylated alkaloids,10 such as lentiginosine (8) and
swainsonine (9) (Fig. 1) resemble the structure of carbohydrates.
Therapeutic potential of these alkaloids as anticancer and antiviral
agents etc. is strongly related to their glycosidase inhibitory activ-
ities.11 Biological activities of these compounds are dependent on
n
n
n
n
4
5
6
7
Scheme 1.
HO
HO
OH
OH
OH
H
N
H
N
H
N
OH
OH
OH
(+)-lentiginosine (8)
(−)-swainsonine (9)
(+)-swainsonine (ent-9)
* Corresponding author. Tel.: þ886 2 3366 1651; fax: þ886 2 2363 6359; e-mail
address: ymtsai@ntu.edu.tw (Y.-M. Tsai).
Fig. 1. Some representative polyhydroxylated indolizidines.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.048

M.-J. Chen, Y.-M. Tsai / Tetrahedron 67 (2011) 1564e1574
1565
the chiralities of the hydroxyl substituents. Thus while the naturally
occurring -man-
-(ꢀ)-swainsonine (9) is a potent inhibitor of
osidases,12 it has no effect on the -rhamnosidase.13 On the con-
trary, the mirror image of 9,
-(þ)- swainsonine (ent-9), is a potent
inhibitor of nariginase (an -rhamnosidase) but with no or low
inhibition for
-manosidases.13 The stereochemical complexity of
HO
a
OH
H
N
D
a-D
a-L
OH
b
L
a-L
a
b
(+)-swainsonine (ent-9)
D
the structures and their diverse biological activities attracted con-
siderable interest in the synthesis of this class of compounds.10
Previously we have demonstrated that the radical chemistry of
acylsilane (Scheme 2) could be useful in the construction of silyloxy
substituted pyrolizidinones, indolizidinones, and quinolizidinones
(12).14 More recently, we successfully employed this method in the
synthesis of (þ)-lentiginosine (8), (þ)-1,2-di-epi-swainsonine (15)
and (þ)-1,8a-di-epi-lentiginosine (16).15 In the present study, we
disclose the synthesis of (þ)-swainsonine (ent-9) and some qui-
nolizidinones using this method.
BzO
O
H
O
N
N
O
O
17
21
BzO
O
SPh
X
O
O
O
N
OΣ
N
Σ
SPh
2
Σ
3
Bu3SnH
O
O
18
22
n
N
Σ
n
AIBN
n
N
Σ
N
PhH, Δ
n
n
n
O
O
O
O
O
OH
10
11
12
O
n = 1 or 2, Σ = SiR3
COOH
O
O
O
S
S
S
S
OAc
H
+
H2N
NH2
+
O
PhS
Σ
Σ
3
2
O
O
OAc
19
20
23
24
8
N
MePh2Si
3
Σ = SiMe3
O
H
13
Scheme 3.
S
OH
O
O
OH
OH
PhO
O
O
N
H
N
appeared as a singlet at
d 5.10 (in CDCl3). Based on the fact that
there is no coupling between C(3) and C(4), we assumed that the
two hydrogens adopted a trans relationship in the five-membered
ring.
or
OH
OH
N
Σ
3
O
14
15
16
Originally we attempted to replace the hydroxyl group with
a phenylthio group so that the thio group could be used to generate
Σ = SiMe3
an a
-acylamino radical.19 However, due to the presence of an acid
Scheme 2.
sensitive isopropylidene protecting group, exchanging the hydroxyl
group of 27 with thiophenol under acidic condition was not suc-
cessful. We therefore took a different approach by converting lac-
tam carbinol 27 to thiocarbonate 28 (80%).20 Hydrolysis21 of the
dithiane moiety in 28 with iodobenzene bistrifluoroacetate in wet
acetonitrile gave acylsilane 14 in 91% yield. Radical cyclization re-
action was accomplished by treatment of 14 with tributyltin hy-
dride (TBTH) and catalytic amount of azobisisobutyronitrile (AIBN)
in refluxing benzene, and the crude product was directly desily-
lated in THF with tetrabutylammonium fluoride (TBAF) to give an
isomeric mixture of alcohols 29 (isomer ratio¼6/4; 91% yield).
Alcohols 29 were oxidized with DesseMartin periodinane22
(DMP) to yield ketone 30 (99%) as a single isomer. This indicated
that the two isomers of 29 were epimeric at C(8). Although the
stereochemical control at C(8) was not satisfactory, the stereo-
center at C(8a) was obtained in only one form. Similar to the report
2. Results and discussion
As shown in Scheme 3, there are two possible routes for the
synthesis of (þ)-swainsonine using the acylsilane radical cycli-
zation approach. These two routes are differentiated by the
manner of ring constructions. In route-a, a six-membered ring is
formed through an
chiral centers at C(1) and C(2) come from a chiral template 20
derived from -ribose. In contrast, route-b involves the forma-
a-acylamino radical cyclization, and the
D
tion of a five-membered ring with a commercially available
carboxylic acid 23 as chiral template.
2.1. The first approach of (D)-swainsonine
of Dener et al.,23 the
a-acylamino radical generated from thicar-
We started from the route-a approach as shown in Scheme 4.
2-Trimethylsilyl-1,3-dithiane (25) was alkylated with bromide 2616
followed by phenylhydrazine treatment to give amine 19 in 76%
yield.17 This amine reacted with the commercially available 2,3-
bonate 14 prefers to attack the acylsilane from the face opposite to
the adjacent CeO bond. To confirm the stereochemistry at the
ring junction, the alcohol mixture 29 was treated sequentially
with sodium hydride, carbon disulfide, and methyl iodide at 0 ꢁC to
afford a xanthate mixture. The crude xanthate mixture was then
reduced with TBTH in refluxing benzene to give the known indo-
lizidinone 3124 in 68% yield. This Barton deoxygenation process25
therefore identified the C(8a) stereochemistry of alcohols 29.
isopropylidene- -ribono-1,4-lactone (20), and the resulting crude
D
amide diol was cleaved with lead tetraacetate followed by acid
promoted cyclization of the intermediate amide aldehyde to afford
a single isomer of lactam carbinol 27 in 84% yield over three steps.18
In the proton NMR spectrum of 27, the hemiaminal hydrogen (C(4))

1566
M.-J. Chen, Y.-M. Tsai / Tetrahedron 67 (2011) 1564e1574
1. BuLi then
Br
2.2. The second approach of (D)-swainsonine
N
1. 20, MeOH
2. Pb(OAc)4
K2CO3
CHPh
(26)
S
S
S
S
H
3
To further demonstrate the potential synthetic utility of our
methodology led us to pursue the total synthesis of (þ)-swainso-
nine (ent-9) in the synthetic pathway b. As shown in Scheme 5,
Mitsunobu coupling29 of alcohol 3330 with phthalimide afforded
imide 34 in 95% yield. Imide 34 was deprotected by hydrazine to
produce the crude amine 24.31 This amine was then reacted with
acid chloride 35, prepared from acid 23 by mixing with oxalyl
chloride, to provide lactone 36 (65%). Rearrangement of lactone 36
to glutarimide 37 was achieved via potassium tert-butoxide treat-
ment at low temperature in 91% yield.32
NH2
Σ
Σ
2. PhNHNH2
(76%)
3
3. AcOH
25
19
(84%)
Σ = SiMe3
S
O
HO
O
PhO
S
O
N
PhOCSCl
O
O
PhI(OCOCF3)2
O
S
S
DIPEA
N
DMAP
(91%)
Σ
3
(80%)
S
3
O
Σ
O
27
28
O
O
1. hydrazine
HO
O
H
2. NEt3
(65%)
H
O
PhO
O
N
S
S
1
PPh3, DIAD
phthalimide
(95%)
1. TBTH
AIBN
S
S
N
8
HO
O
O
8a
N
Σ
Σ
2
1. NaH
CS2
MeI
2. TBAF
2
Cl
2
(91%)
exo/endo
= 6/4
33
34
O
O
Σ
O
3
14
O
O
Σ = SiMe3
O
O
(35)
29
2. TBTH
AIBN
HO
O
(68%)
DMP
O
S
H
1. NaBH4
S
H
t-BuOK
(91%)
O
N
(99%)
H
O
H
N
2. p-TsOH
S
2 Σ
O
O
S
O
PhSH
O
2 Σ
37
O
(73%)
N
36
N
OH
H
O
HO
BzO
30
O
31
SPh
SPh
OH
S
S
PhI(OCOCF3)2
(80%)
BzCl
N
ref 26
O
NaH
DMAP
(50%)
N
N
N
PhNTf2
S
S
16
(95%)
2 Σ
2 Σ
O
O
38
39
TfO
O
PdCl2(PPh3)2
formic acid
NEt3
BzO
BzO
BzO
H
O
O
SPh
OH
ent-9
H
N
1. Bu3SnH
ACCN
N
N
O
ref 24
Martin
sulfurane
(73%)
(79%)
O
2. TBAF
O
32
17
Σ
N
2
(86%)
Scheme 4.
O
O
40
41
21
O
BzO
BzO
OAc
OAc
OAc
OAc
H
H
1. OsO4
NMO
BH3
Note that indolizidinone 31 had been converted to (þ)-1,8a-di-epi-
lentiginosine (16) by Heitz and Overman.26
NaOH
MeOH
(87%)
ent-9
2. Ac2O
DMAP
(80%)
N
N
In the 1H NMR spectrum of the major isomer of 29, the ring
42
43
(55%)
O
junction hydrogen (H(8a)) at
d 3.16 (in C6D6) appears as a doublet
(d.r. = 10/1)
(J¼9.6 Hz). The large coupling constant indicates a trans-diaxial
relationship between H(8) and H(8a) in the pseudo-chair confor-
mation of the piperidine portion of the structure. In contrast, H(8a)
Scheme 5.
Sodium borohydride reduction of glutarimide 37 selectively
reduced the more reactive carbonyl group.33 Stirring the crude
carbinol with thiophenol under acidic condition provided sulfide
38 in 73% yield over two steps. This sulfide appeared to be a pair of
diastereomers (2.8/1) epimeric at the newly constructed chiral
center. In order to inhibit the generation of acyliminium ion during
the dithiane hydrolysis process, we converted the hydroxyl group
to a benzoate as an electron-withdrawing group by Wolfe’s con-
dition34 and obtained benzoate 39 in 95% yield. Hydrolysis21 of the
dithiane moiety of 39 under the condition stated above gave acyl-
silane 40 (80%) successfully without touching the phenylthio group.
Radical cyclization reaction of 40 proceeded with TBTH and
catalytic amount of 1,10-azobis(cyclohexanecarbonitrile) (ACCN) in
refluxing toluene to produce the crude silyl ethers that was desi-
lylated to afford alcohols 41 in 86% yield over two steps. As dis-
cussed above, at this stage we assumed that the ring junction
stereochemistry was constructed very selectively, and H(8a) was
of the minor isomer at
d 3.27 (in C6D6) appears as a narrow broad
singlet indicating a very small coupling with H(8). We therefore
assigned the major isomer of 29 as the exo isomer. In addition,
sodium borohydride reduction of ketone 30 in methanol at ꢀ40 ꢁC
gave exo-29 (70%) selectively. This is consistent with an axial attack
of the hydride to the carbonyl and placed H(8) at the pseudo-axial
position.
For the synthesis of (þ)-swainsonine (ent-9), ketone 30 was
treated with sodium hydride in the presence of N-phenylbis(tri-
fluoromethanesulfonimide) to give selectively enol triflate 32
(50%),27 which contains a thermodynamically more stable conju-
gated structure. Removal of the triflate moiety by using bis(tri-
phenylphosphine)palladium(II) dichloride, triethylamine, and
formic acid28 afforded the key olefin intermediate 17 (79%). This
material was subsequently converted to ent-9 as previously de-
scribed in the literature.24 Up to this point, we have achieved
a formal synthesis of (þ)-swainsonine.

M.-J. Chen, Y.-M. Tsai / Tetrahedron 67 (2011) 1564e1574
1567
syn to the adjacent benzoyloxy group. The chiral center at C(1) was
1. BuLi
then 26
S
NEt3, 35
not well-controlled and gave us a pair of epimers. Due to the dif-
ficulty in distinguishing exo/endo isomers of 41 from spectroscopic
data, we did not further explore the exo/endo ratio in detail. De-
hydration of the alcohol mixture 41 by Martin sulfurane35 gave
a 73% yield of olefin 21 and a trace amount of the regioisomer. This
result confirmed the above assumption that 41 was an epimeric
mixture at C(1).
Dihydroxylation of 21 was accomplished by catalytic amount of
osmium tetroxide in the presence of N-methylmorpholine-N-oxide
(NMO),36,37a and the resulting crude diol was acetylated to give ester
42 (55%). Ester 42 is a mixture of two diastereomers (10/1) pre-
sumably derived from the attack of osmium tetroxide from the
two faces of the double bond. Acetylation is necessary for the ease of
purification. Unfortunately, the two isomers of 42 could not be sep-
arated by column chromatography. However, we found that redu-
cing the lactam carbonyl group allowed us to separate the resulting
isomers. Thus, borane reduction of 42 followed by chromatographic
purification afforded the major ester 43 in 80% yield. The synthesis
of (þ)-swainsonine (ent-9) was achieved by removal of the ester
groups of 43 by sodium hydroxide treatment in methanol in 87%
yield. The spectroscopic data for synthetic ent-9 were the same as
the literature data.24 This also helped us to determine the stereo-
chemistry of the major isomer at the dihydroxylation step. The
stereoselectivity is consistent with literature precedents.37
S
S
H
NH2
(66%)
2. PhNHNH2
(91%)
S
Σ
Σ
44
45
Σ = SiPh2Me
OH
O
O
S
S
O
t-BuOK
(89%)
H
H
O
N
3
N
S
S
3
Σ
Σ
46
O
47
OH
OH
PhS
S
O
S
1, NaBH4
+
N
N
2, p-TsOH
S
S
PhSH
3
3
Σ
Σ
O
SPh
48
49
(79%)
(4%)
OBz
OBz
PhS
S
PhS
BzCl
PhI(OCOCF3)2
(91%)
DMAP
O
48
N
N
(92%)
S
Σ
3
3
Σ
O
O
50
51
X
OBz
OBz
Y
H
N
Bu3SnH
2.3. Formal synthesis of (L)-epiquinamide
O
+
ACCN
(77%)
N
Σ
In addition to polyhydroxylated indolizidines, quinolizidines
can also be synthesized this way. As shown in Scheme 6, 2-meth-
yldiphenylsilyl-1,3-dithiane (44)4 was alkylated with bromide 2616
followed by phenylhydrazine deprotection to afford amine 45 in
91% yield.17 Amine 45 was treated with acid chloride 35 prepared as
above to afford amide 46 in 66% yield. Rearrangement of 46 using
potassium tert-butoxide provided imide 47 (89%).32 Reducing the
carbonyl group of 47 followed by exchanging the newly formed
hydroxyl group with thiophenol gave sulfides 48 and 49 in 79% and
4% yield, respectively. The regioselectivity of reduction is lower
than the succinimide system mentioned above. The sulfides
obtained are mixtures of two epimers.
O
O
53
(9%)
X = OΣ, Y = H
52a
52b X = H, Y = OΣ
52a/52b = 1.3
Scheme 6.
OBz
O
X
OBz
O
H
Y
H
N
Benzoylation34 of sulfides 48 (92%) followed by hydrolysis21 of
the dithiane moiety afforded acylsilane 51 (91%). Radical cyclization
of 51 with TBTH and ACCN in refluxing toluene provided quinoli-
zidinones 52 (52a/52b¼1.3/1) and uncyclized reduction product 53
in 77% and 9% yield, respectively. Surprisingly, TBAF desilylation of
52 caused partial transferring of the benzoyl group to the hydroxyl
group. Thus, instead we treated 52 with methanol in the presence
of TsOH (Scheme 7) and successfully removed the silyl group to
yield alcohols 54 (100%) without any acyl migration. Although we
were not able to separate the two epimers in 54, the major isomer
could be identified as 54a by comparing with the literature data.38
The other isomer 54b could be obtained in 55% yield by treating
the alcohol mixture through DMP oxidation22 and L-Selectride
reduction in sequence. The bulky reducing agent selectively do-
nates hydride from the equatorial face of the 3-azacyclohexanone
structure to produce 54b. In contrast, Marquart et. al.38 already
demonstrated that reduction of the same ketone substrate using
sodium borohydride gave 54a as the sole product.
1. (Im)2C=S
2. Bu3SnH
AIBN
p-TsOH
MeOH
52
(100%)
N
(61%)
55
1. DMP
54a X = OH, Y = H
2. L-Selectride
(55%)
54b
X = H, Y = OH
OH
H
NHAc
H
N
NaOH
MeOH
ref 42
(69%)
N
O
56
(−)-epiquinamide (57)
Scheme 7.
(20%).39 As we have reported previously,40 phenyl groups on silicon
facilitates the radical cyclization reaction. This effect is particularly
helpful in this quinolizidinone system.
Again, a very high stereoselectivity at the ring junction was
obtained during the radical cyclization step, and the stereochemical
course is the same as the above mentioned cases. Although the
stereoselectivity at C(9) is low, the chirality at C(9) can be attenu-
ated through an oxidationereduction sequence. In this system,
switching the silyl group to a trimethylsilyl group showed a lower
cyclization yield (68%) accompanied by a higher reduction yield
Barton deoxygenation process25 of 54 as mentioned above
afforded benzoate 55 (61%). Removal of the ester group under basic
condition provided a known alcohol 56 (69%).41 Note that alcohol
56 was a synthetic intermediate in the synthesis of (ꢀ)-epi-
quinamide (57),41 whose enantiomer is a natural product isolated
recently from an Ecuadorian frog Epipedobates tricolor.42e45

1568
M.-J. Chen, Y.-M. Tsai / Tetrahedron 67 (2011) 1564e1574
3. Conclusion
was dissolved in CH3CN (100 mL), cooled in an ice-water bath fol-
lowed by the addition of K2CO3 (2.47 g, 17.9 mmol) and Pb(OAc)4
(7.94 g, 17.9 mmol) sequentially. The resulting mixture was stirred
at the same temperature for 30 min and then at rt for another
30 min. The reaction mixture was filtered and concentrated to give
a liquid residue. The residue was dissolved in CH2Cl2 (100 mL)
followed by the addition of AcOH (0.7 mL), stirred at rt for 13 h and
then concentrated to give a solid. The solid was chromatographed
We have demonstrated a versatile synthetic method in the
synthesis of polyhydroxylated indolizidines and quinolizidines via
a
-acylamino radical cyclizations with acylsilanes. The key radical
cyclization step constructed the fused bicyclic structure with good
efficiency and stereo-control at the ring junction position. This
methodology can easily adopt existing chiral building blocks and is
quite versatile in the way of bond constructions. The flexibility was
exemplified in the two approaches for the synthesis of (þ)-swain-
on silica gel (hexane/EtOAc, 7:3) to yield 5.53 g (84%) of 27 as
19
a white solid: [
a
]
D
ꢀ4.0 (c 2.3, CHCl3); mp 77e78 ꢁC; IR (CH2Cl2)
sonine (ent-9). Similarly,
a
formal synthesis of quinolizidine
3350 (br), 1693 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d 0.16 (s, 9H, TMS),
(ꢀ)-epiquinamide (57) was also accomplished. In addition, several
synthetic intermediates obtained along the way in the synthesis
exhibit the potential to be converted to other polyhydroxylated
indolizidines and quinolizidines. This work successfully extended
the synthetic utility of acylsilanes both in the synthesis of struc-
turally complex acylsilanes and their applications.
1.35 (s, 3H), 1.40 (s, 3H), 1.65e1.96 (m, 3H), 1.97e2.06 (m, 1H),
2.10e2.22 (m, 2H), 2.41 (dt, J¼14.2, 3.6 Hz, 2H, equatorialeSCH2),
2.93e3.04 (m, 2H, axialeSCH2), 3.21 (dt, J¼13.8, 6.8 Hz, 1H, NCH2),
3.52 (dt, J¼13.8, 6.8 Hz, 1H, NCH2), 4.52 (d, J¼5.4 Hz, 1H, C(4)H),
4.81 (d, J¼5.4 Hz, 1H, C(3)H), 5.10 (s, 1H, NCHO); 13C NMR (CDCl3,
100 MHz)
d
ꢀ1.9 (CH3), 23.7 (CH2), 25.3 (CH2), 25.5 (CH2), 26.0
(CH3), 27.4 (CH3), 34.7 (CH2), 38.4 (C), 40.5 (CH2), 76.9 (CH), 79.5
(CH), 84.5 (CH), 112.9 (C), 171.4 (C); HRMS (EI) calcd for
C17H31NO4S2Si 405.1458, found 405.1462.
4. Experimental section
4.1. General
4.4. (L)-(3R,4S,5R)-3,4-(Isopropylidenedioxy)-5-
(phenoxythiocarbonyloxy)-1-[3-(2-trimethylsilyl-1,3-dithian-
2-yl)propyl]pyrrolidin-2-one (28)
Melting points are uncorrected.1H NMR spectrawere recorded at
400 MHz; 13C NMR spectra were recorded at 100 MHz. Choroform
(
d
¼7.24 ppm) was used as internal standard in 1H NMR spectra,
whereas CDCl3
(
d
¼77.0 ppm) was used as internal standard in 13C
To a solution of 27 (437 mg, 1.08 mmol), diisopropylethylamine
(0.26 mL, 1.6 mmol) and DMAP (12 mg, 0.11 mmol) in CH2Cl2
(10 mL) at rt was added slowly O-phenyl chlorothioformate
(0.18 mL, 1.3 mmol). The resulting mixture was stirred at the same
temperature for 2 h, concentrated and chromatographed on silica
NMR spectra. When benzene-d6 was used as NMR solvent, benzene,
and benzene-d6 was used as internal standard for 1H (
and 13C NMR (
d
¼7.16 ppm)
d
¼128.4 ppm) spectra, respectively. Benzene and THF
were distilled from sodium benzophenone ketyl under N2. Trie-
thylamine, diisopropylethylamine, dichloromethane, N,N-dime-
thylformamide, and toluene were dried with CaH2 and distilled. The
solvent used for cyclization reactions was deoxygenated by passing
a gentle stream of argon through for 0.5 h before use. All reactions
were performed under a blanket of N2 or Ar.
gel (hexane/EtOAc, 7:3) to give 464 mg (80%) of 28 as a colorless
20
liquid: [
a
]
ꢀ14.4 (c 2.2, CHCl3); IR (CH2Cl2) 1716 cmꢀ1
;
1H NMR
D
(CDCl3, 400 MHz)
d 0.17 (s, 9H, TMS), 1.38 (s, 3H), 1.44 (s, 3H),
1.68e1.94 (m, 3H), 1.96e2.05 (m, 1H), 2.13e2.24 (m, 2H), 2.40 (br d,
J¼14.0 Hz, 2H, equatorialeSCH2), 2.93e3.04 (m, 2H, axialeSCH2),
3.10e3.20 (m, 1H, NCH2), 3.75 (dt, J¼13.8, 7.6 Hz, 1H, NCH2), 4.83 (d,
J¼6.0 Hz, 1H, C(4)H), 4.89 (d, J¼6.0 Hz, 1H, C(3)H), 5.12 (s, 1H,
NCHO), 7.13 (d, J¼8.0 Hz, 2H), 7.25 (t, J¼8.0 Hz,1H), 7.37 (t, J¼8.0 Hz,
4.2. 2-(3-Aminopropyl)-2-trimethylsilyl-1,3-dithiane (19)
To a solution of 25 (8.70 g, 45.2 mmol) in THF (45 mL) cooled in
a dry ice-acetone bath was added over 25 min a 1.6 N BuLi solution
in hexane (29 mL, 47 mmol). The resulting solution was stirred at
the same temperature for another 30 min followed by the addition
of a solution of 26 (10.2 g, 44.9 mmol) in THF (45 mL) over 30 min.
The resulting mixture was slowly warmed up to rt and then stirred
overnight. The reaction mixture was poured into water and
extracted with EtOAc. The organic layer was washed with brine,
dried (MgSO4), and concentrated to give a liquid residue. The liquid
was dissolved in EtOH (67 mL) followed by the addition of phe-
nylhydrazine (4.50 mL, 45.4 mmol) and then stirred at rt for 3.5 h.
The resulting mixture was concentrated in vacuo, and the residue
was chromatographed on silica gel (MeOH/concd NH3, 9:1) to give
2H); 13C NMR (CDCl3, 100 MHz)
d
ꢀ2.1 (CH3), 23.5 (CH2), 24.9 (CH2),
25.1 (CH2), 26.0 (CH3), 27.3 (CH3), 34.3 (CH2), 38.3 (C), 41.1 (CH2),
67.3 (CH), 76.9 (CH), 79.5 (CH),112.9 (C),120.5 (CH),126.1 (CH),129.1
(CH), 149.9 (C), 166.1 (C), 170.4 (C); HRMS (EI) calcd for
C24H35NO5S3Si 541.1441, found 541.1440.
4.5. General procedure for dithiane hydrolysis using
iodobenzene bistrifluoroacetate: (L)-(3R,4S,5R)-3,4-
(isopropylidenedioxy)-5-(phenoxythiocarbonyloxy)-1-[4-oxo-
4-(trimethylsilyl)butyl]pyrrolidin-2-one (14)
To a mixture of 28 (570 mg, 1.05 mmol), NaHCO3 (352 mg,
4.19 mmol), water (2.6 mL), and CH3CN (10.5 mL) was added
iodobenzene bistrifluoroacetate (837 mg, 1.95 mmol) in one por-
tion. The resulting mixture was stirred at rt for 23 min and then
poured into water and extracted with EtOAc. The organic layer was
washed with brine, dried (MgSO4), concentrated, and chromato-
8.54 g (76%) of 19 as a pale yellow liquid: IR (neat) 3370 (br) cmꢀ1
;
1H NMR (C6D6, 400 MHz)
d
0.33 (s, 9H, TMS), 1.13 (br s, 2H, NH2),
1.40e1.45 (m, 1H), 1.58e1.78 (m, 3H), 2.06 (dt, J¼14.6, 3.2 Hz, 2H,
equatorialeSCH2), 2.23e2.30 (m, 2H), 2.53 (t, J¼6.6 Hz, 2H, NCH2),
2.73 (td, J¼14.6, 3.2 Hz, 2H, axialeSCH2); 13C NMR (C6D6, 100 MHz)
d
ꢀ1.6 (CH3), 24.0 (CH2), 26.0 (CH2), 32.4 (CH2), 35.7 (CH2), 39.6 (C),
graphed on silica gel (hexane/EtOAc, 65:35) to give 434 mg (91%) of
24
43.3 (CH2); HRMS (EI) calcd for C10H23NS2Si 249.1041, found
249.1042.
14 as a yellow oil: [
a
]
D
ꢀ25.9 (c 2.3, CHCl3); IR (CH2Cl2) 1718,
1645 cmꢀ1
;
1H NMR (CDCl3, 400 MHz)
d 0.17 (s, 9H, TMS), 1.37 (s,
3H), 1.43 (s, 3H), 1.64e1.78 (m, 1H), 1.82e1.97 (m, 1H), 2.56e2.72
(m, 2H, COCH2), 3.11 (ddd, J¼13.4, 8.0, 4.6 Hz, 1H, NCH2), 3.62 (dt,
J¼13.4, 8.0 Hz, 1H, NCH2), 4.74 (d, J¼6.0 Hz, 1H, C(4)H), 4.87 (d,
J¼6.0 Hz, 1H, C(3)H), 5.06 (s, 1H, NCHO), 7.13 (d, J¼8.0 Hz, 2H), 7.23
(t, J¼8.0 Hz, 1H), 7.36 (t, J¼8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
4.3. (L)-(3R,4S,5R)-5-Hydroxy-3,4-(isopropylidenedioxy)-1-[3-
(2-trimethylsilyl-1,3-dithian-2-yl)propyl]pyrrolidin-2-one (27)
To a solution of 19 (3.06 g, 16.3 mmol) in MeOH (40 mL) was
added 20 (5.07 g, 20.4 mmol), and the resulting solution was stirred
at rt overnight and then concentrated to give a liquid. The liquid
d
ꢀ3.0 (CH3), 19.1 (CH2), 25.9 (CH3), 27.3 (CH3), 40.3 (CH2), 44.8
(CH2), 67.5 (CH), 77.0 (CH), 79.8 (CH), 113.1 (C),120.9 (CH), 126.5

M.-J. Chen, Y.-M. Tsai / Tetrahedron 67 (2011) 1564e1574
1569
(CH), 129.4 (CH), 150.4 (C), 166.7 (C), 171.0 (C), 245.7 (C); HRMS (ESI)
4.8. (L)-(1R,2R,8aS)-1,2-(Isopropylidenedioxy)-1,6,7,8a-
tetrahydro-3,8(2H,5H)-indolizindione (30)
calcd for C17H31NO4S2Si (MþNa)þ 474.1383, found 474.1382.
4.6. (1R,2R,8R/S,8aR)-8-Hydroxy-1,2-(isopropylidenedioxy)-
1,5,6,7,8,8a-hexahydro-2H-indolizin-3-one (29)
To a solution of 29 (132 mg, 0.581 mmol) in CH2Cl2 (6 mL) was
added a 0.5 M DesseMartin periodinane solution in CH2Cl2 (1.8 mL,
0.90 mmol). The reaction mixture was stirred at rt for 2 5 h and
then poured into a saturated NaHCO3 solution and extracted with
CH2Cl2. The organic layer was washed with a saturated Na2S2O3
solution, dried (MgSO4), concentrated, and chromatographed on
To a refluxing solution of 14 (1.29 g, 2.85 mmol) in toluene
(14.5 mL) was added over 6 h using a syringe pump a solution of
TBTH (1.20 mL, 4.46 mmol) and AIBN (70 mg, 0.43 mmol) in toluene
(14.5 mL). The resulting mixture was stirred at the same temper-
ature for 1.3 h and then concentrated in vacuo because the reaction
was not complete, the above procedure was repeated using 0.80 mL
(2.97 mmol) of TBTH and 70 mg (0.43 mmol) of AIBN with an ad-
dition time of 2 h. The reaction mixture was stirred at the same
temperature for another 2 h and then concentrated and chroma-
tographed on silica gel (EtOAc/MeOH, 95:5) to give 589 mg (91%) of
29 (exo/endo¼6:4) as a pale yellow oil: IR (CHCl3) 3388 (br),
silica gel (EtOAc) to give 130 mg (99%) of 30 as a pale yellow oil:
20
[
a
]
ꢀ60.6 (c 9.9, CHCl3); IR (CH2Cl2) 1708 cmꢀ1
;
1H NMR (CDCl3,
d 1.34 (s, 3H), 1.41 (s, 3H), 1. 84e1.96 (m, 1H), 2.03e2.14
D
400 MHz)
(m, 1H), 2.45e2.60 (m, 2H, COCH2), 3.17 (ddd, J¼13.2, 9.2, 4.4 Hz,
1H, NCH2), 4.03 (d, J¼1.2 Hz, 1H, NCH), 4.11 (dt, J¼13.2, 5.2 Hz, 1H,
NCH2), 4.54 (d, J¼6.4 Hz 1H, C(2)H), 5.04 (dd, J¼6.4, 1.2 Hz, 1H, C(1)
H); 13C NMR (CDCl3, 100 MHz)
d 24.3 (CH2), 25.3 (CH3), 26.9 (CH3),
39.1 (CH2), 39.4 (CH2), 68.7 (CH), 72.3 (CH), 77.1 (CH), 112.8 (C),
168.0 (C), 201.7 (C); HRMS (ESI) calcd for C11H15NNaO4 (MþNa)þ
248.0899, found 248.0891.
1697 cmꢀ1; 1H NMR (C6D6, 400 MHz)
d
0.83 (br d, J¼15.2 Hz, 0.4H),
0.87e1.07 (m, 2H), 1.27 (s, 1.8H), 1.28 (s, 1.2H), 1.42e1.54 (m over-
lapped with two s at 1.44 and 1.46, 3.6H),1.61e1.71 (m,1H),1.99 (td,
J¼12.8, 3.2 Hz, 0.6H, NCH2 of exo isomer), 2.14 (td, J¼12.8, 4.0 Hz,
0.4H, NCH2 of endo isomer), 2.61e2.71 (m, 1.2H), 3.16 (d, J¼9.6 Hz,
0.6H, NCH of exo isomer), 3.25 (br s, 0.4H, OH), 3.27 (br s, 0.4H, NCH
of endo isomer), 3.54 (br s, 0.4H, C(8)H of endo isomer), 3.96 (dd,
J¼12.8, 4.0 Hz, 0.6H, NCH2 of exo isomer), 4.08 (dd, J¼12.8, 4.8 Hz,
0.4H, NCH2 of endo isomer), 4.45 (d, J¼6.6 Hz, 0.6H, C(1)H of exo
isomer), 4.56 (d, J¼6.6 Hz, 0.6H, C(2)H of exo isomer), 4.60 (d,
J¼6.6 Hz, 0.4H, C(1)H of endo isomer), 4.85 (d, J¼6.2 Hz, 0.4H, C(2)H
of endo isomer); HRMS (ESI) calcd for C11H18NO4 (MþH)þ 228.1236,
found 228.1231.
4.9. (D)-(1R,2R)-1,2-(Isopropylidenedioxy)-8-
(trifluoromethanesulfonyloxy)-1,5,6,7-tetrahydro-2H-
indolizin-3-one (32)
To a mixture of a 60% NaH dispersion (12.5 mg, 0.313 mmol) in
THF (2 mL) cooled in an ice-water bath was added a solution of 30
(59 mg, 0.26 mmol) and N-phenylbis(trifluoromethanesulfonimide)
(186 mg, 0.52 mmol) in THF (1 mL). The resulting mixture was
stirred at rt for 3 h and then poured into water and extracted with
CH2Cl2. The organic layer was dried (MgSO4), concentrated, and
Pure exo-29 (8R-isomer) was obtained by reduction of 50 mg
(0.22 mmol) of 30 by NaBH4 (50.4 mg, 1.32 mmol, added over three
portions) in MeOH cooled in a dry ice-CH3CN bath in a period of
30 min. The reaction mixture was quenched by the addition of
saturated NaHCO3 solution and extracted with CH2Cl2. The organic
layer was dried (MgSO4), concentrated, and chromatographed on
chromatographed on silica gel (hexane/EtOAc, 6:4) to give 46.4 mg
24
(50%) of 32 as a white solid: [
a
]
þ88.7 (c 2.3, CHCl3); mp
D
102e104 ꢁC; IR (CHCl3) 1742, 1710 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
1.41 (s, 3H), 1.43 (s, 3H), 1.89e2.05 (m, 2H), 2.48e2.63 (m, 2H, C(7)
d
H), 3.45 (ddd, J¼13.2, 8.4, 4.4 Hz, 1H, NCH2), 3.61 (ddd, J¼13.2, 6.4,
4.4 Hz,1H, NCH2), 4.71 (d, J¼6.4 Hz,1H, C(1)H), 5.28 (d, J¼6.4 Hz,1H,
silica gel (EtOAc) to give 35 mg (70%) of exo-29 as a white solid:
C(2)H); 13C NMR (CDCl3, 100 MHz)
d 20.2 (CH2), 25.3 (CH2), 25.7
20
[
a]
ꢀ72.9 (c 3.0, CHCl3); mp 146e148 ꢁC; IR (neat) 3390 (br),
(CH3), 26.8 (CH3), 38.2 (CH2), 70.7 (CH), 76.2 (CH), 114.4 (C), 118.2
(quartet, JCeF¼317.0 Hz), 129.5 (C), 132.4 (C), 169.0 (C); HRMS (EI)
calcd for C12H14F3NO6S 357.0488, found 357.0481.
D
1682 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d 1.38 (s, 3H), 1.41e1.52 (m
overlapped with s at 1.45, 4H), 1.66e1.90 (m, 3H), 2.16 (br d,
J¼9.6 Hz, 1H), 2.63 (td, J¼12.8, 3.6 Hz, 1H, NCH2), 3.13e3.27 (m, 2H),
4.10 (br d, J¼12.8 Hz, 1H, NCH2), 4.62 (d, J¼6.6 Hz, 1H), 4.71 (d,
4.10. (D)-(1R,2R)-1,2-(Isopropylidenedioxy)-1,5,6,7-
tetrahydro-2H-indolizin-3-one (17)
J¼6.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d 23.8 (CH2), 25.3 (CH3),
26.7 (CH3), 33.6 (CH2), 39.6 (CH2), 67.6 (CH), 69.6 (CH), 74.6 (CH),
77.5 (CH), 112.6 (C), 168.7 (C); HRMS (ESI) calcd for C11H18NO4
(MþH)þ 228.1236, found 228.1231.
A mixture of 32 (26 mg, 0.070 mmol), bis(triphenylphosphine)
palladium(II) dichloride (5.5 mg, 0.0078 mmol), Et3N (30
mL,
0.22 mmol), and formic acid (6.0
mL, 0.16 mmol) in DMF (0.7 mL) was
4.7. (L)-(1R,2R,8aR)-1,2-(Isopropylidenedioxy)-1,5,6,7,8,8a-
hexahydro-2H-indolizin-3-one (31)26
heated at 60 ꢁC for 22 h and then directly concentrated in vacuo and
chromatographed on silica gel (hexane/EtOAc, 4:6) to give 12 mg
(79%) of 17 as a yellow solid: [
The spectroscopic data is identical to that reported for the racemic
a
]
21 þ79.9 (c 1.4, CHCl3); mp 57e59 ꢁC.
D
To a solution of 29 (78 mg, 0.34 mmol) inTHF (3.4 mL) cooled in an
ice-waterbathwasadded a60% NaHdispersion(15 mg, 0.38mmol)in
one portion. The reaction mixture was stirred at the same tempera-
ture for 10 min and then at rt for 30 min. The resulting mixture was
mixture.24
4.11. N-[2-(2-Trimethylsilyl-1,3-dithian-2-yl)ethyl]
cooled in an ice-water bath followed by slow addition of CS2 (31
0.51 mmol). The reaction mixture was stirred at the same tempera-
ture for 1 h followed by the addition of MeI (32 L, 0.51 mmol). The
m
L,
phthalimide (34)
m
To a solution of 33 (2.36 g, 10.0 mol), phthalimide (1.47 g,
10.0 mmol), and triphenylphosphine (2.88 g, 11.0 mmol) in THF
(40 mL) cooled in an ice-water bath was added over 15 min a so-
lution of diisopropyl azodicarboxylate (2.2 mL, 11 mmol) in THF
(10 mL). The reaction mixture was stirred at rt for 3 h and then
concentrated and chromatographed on silica gel (hexane/EtOAc,
85:15) to give 3.46 g (95%) of 34 as a white solid: mp 138e139 ꢁC; IR
resulting mixture was stirred at rt for 2 h and then poured into water
and extracted with CH2Cl2. The organic layer was dried (MgSO4) and
concentrated to give an oil residue. The residue was stirred with
tributyltin hydride (0.20 mL, 0.74 mmol) and AIBN (11 mg, 0.07 mol)
in refluxing benzene (3.4 mL) for 2 h. The resulting solution was
concentrated and chromatographed on silica gel (hexane/EtOAc, 2:8)
togive49mg (68%)of 31 asawhitesolid:[
a
]
21 ꢀ35.6 (c3.1, CHCl3);mp
(CHCl3) 1772, 1712 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d 0.30 (s, 9H,
D
106e107 ꢁC [lit.26
[a
]D ꢀ95 (c 1.0, CHCl3); mp 107e108 ꢁC]. The NMR-
TMS), 1.91 (dtt, J¼14.0, 12.4, 3.2 Hz, 1H), 2.08 (br d, J¼14.0 Hz, 1H),
spectroscopic analysis is consistent with literature data.26
2.43e2.56 (m, 4H), 3.17 (ddd, J¼15.0, 13.2, 2.8 Hz, 2H, axialeSCH2),

1570
M.-J. Chen, Y.-M. Tsai / Tetrahedron 67 (2011) 1564e1574
3.80e3.88 (m, 2H, NCH2), 7.66e7.75 (m, 2H), 7.78e7.87 (m, 2H); 13
NMR (CDCl3, 100 MHz)
(CH2), 36.5 (CH2), 36.7 (C), 123.0 (CH), 132.0 (C), 133.8 (CH),
168.0 (C); HRMS (EI) calcd for C17H23NO2S2Si 365.0939, found
365.0951.
C
10 min and then quenched by the addition of a saturated NaHCO3
and extracted with CH2Cl2. The combined organic layers were dried
(MgSO4) and concentrated to give a solid residue. This solid was
dissolved in a mixture of CH2Cl2 (1 mL) and thiophenol (1 mL)
followed by the addition of p-toluenesulfonic acid monohydrate
(33 mg, 0.17 mmol). The reaction mixture was stirred at rt overnight
and then poured into a 15% NaOH solution and extracted with
CH2Cl2. The organic layer was dried (MgSO4), concentrated, and
chromatographed on silica gel (hexane/EtOAc, 4:6) to give 570 mg
(73%) of 38 as a pale yellow oil: IR (CHCl3) 3372 (br), 1646 cmꢀ1; 1H
d
ꢀ2.6 (CH3), 23.2 (CH2), 25.0 (CH2), 34.4
4.12. (L)-(S)-N-[2-(2-Trimethylsilyl-1,3-dithian-2-yl)ethyl]-
tetrahydro-5-oxo-2-furancarboxamide (36)
To a solution of 34 (1.09 g, 2.98 mmol) in dry THF (6 mL) was
added a 1.5 M MeOH solution of hydrazine (6 mL). The resulting
mixture was stirred at 55 ꢁC for 4 h and then poured into water and
extracted with Et2O. The organic layer was washed with brine,
dried (MgSO4), and concentrated to give a crude amine as a pale
yellow oil. To another solution of 23 (412 mg, 3.17 mmol) and one
drop of DMF in CH2Cl2 (8 mL) cooled in an ice-water bath was
added slowly oxalyl chloride (0.32 mL, 3.73 mmol). The resulting
mixture was stirred at rt for 2 h and then directly concentrated to
give a liquid residue. This liquid was dissolved in THF (5 mL), cooled
in a dry ice-acetone bath followed by the addition of Et3N (0.60 mL,
4.3 mmol) and a solution of the crude amine prepared above in THF
(1 mL). The resulting mixture was stirred at rt overnight and then
poured into water and extracted with CH2Cl2. The organic layer was
dried (MgSO4), concentrated, and chromatographed on silica gel
NMR (CDCl3, 400 MHz)
d 0.07 (s, 2.7H, TMS of the minor isomer),
0.21 (s, 6.3H, TMS of the major isomer), 1.71e1.97 (m, 2.7H),
1.98e2.06 (m, 1H), 2.14e2.26 (m, 1.4H), 2.28e2.79 (m overlapped
with br t at 2.74, J¼12.0 Hz, 6.6H), 3.01 (br t, J¼13.4 Hz, 1H,
axialeSCH2), 3.07e3.22 (m overlapped with td at 3.13, J¼12.8,
4.4 Hz, 1H), 3.42 (td, J¼12.4, 8.0 Hz, 0.3H), 3.92 (td, J¼12.4, 4.8 Hz,
0.3H), 4.00 (td, J¼12.8, 4.8 Hz, 0.7H), 4.11e4.20 (m, 1H), 4.58 (br s,
0.3H, NCHS of the minor isomer), 4.77e4.81 (m, 0.7H, NCHS of the
major isomer), 7.25e7.33 (m, 3H), 7.43e7.50 (m, 0.6H), 7.54 (d,
J¼5.6 Hz, 1.4H); HRMS (EI) calcd for C20H31NO2S3Si 441.1286, found
441.1291.
4.15. (6R/S,5S)-5-Benzoyloxy-1-[2-(2-trimethylsilyl-1,3-
dithian-2-yl)ethyl]-6-(phenylsulfenyl)piperidin-2-one (39)
(hexane/EtOAc, 3:7) to give 675 mg (65%) of 36 as a yellow solid:
21
[
a]
ꢀ10.9 (c 2.9, CHCl3); mp 128e129 ꢁC; IR (CH2Cl2) 3434, 1789,
To a solution of 3 (570 mg, 1.29 mmol), DMAP (158 mg,
1.29 mmol) and Et3N (2 mL) in CH2Cl2 (10 mL) was added slowly
benzoyl chloride (0.2 mL, 1.74 mmol). The reaction mixture was
stirred at rt for 2 h and then partitioned between water and CH2Cl2.
The organic layer was dried (MgSO4), concentrated, and chroma-
tographed on silica gel (hexane/EtOAc, 7:3) to give 672 mg (95%) of
D
1710, 1678 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d 0.22 (s, 9H, TMS),
1.82e1.98 (m, 1H), 2.01e2.12 (m, 1H), 2.33e2.55 (m overlapped
with dt at 2.49, J¼14.4, 4.0 Hz, 5H), 2.56e2.65 (m overlapped with t
at 2.57, J¼8.0 Hz, 3H), 3.04 (br t, J¼14.4 Hz, 2H, axialeSCH2),
3.38e3.56 (m, 2H, NCH2), 4.85 (t, J¼7.6 Hz, 1H, CHO), 6.84 (br s, 1H,
NH); 13C NMR (CDCl3, 100 MHz)
d
ꢀ2.1 (CH3), 23.8 (CH2), 25.1 (CH2),
39 as a colorless oil: IR (CH2Cl2) 1720, 1650 cmꢀ1
;
1H NMR (CDCl3,
26.1 (CH2), 27.9 (CH2), 36.4 (CH2), 37.0 (C), 38.3 (CH2), 77.4 (CH),
168.5 (C), 175.0 (C); HRMS (EI) calcd for C14H25NO3S2Si 347.1045,
found 347.1052.
400 MHz) 0.15 (s, 3.6H, TMS of the minor isomer), 0.19 (s, 5.4H,
d
TMS of the major isomer), 1.72e1.93 (m, 1.4H), 1.95e2.06 (m, 0.6H),
2.08e2.34 (m, 2H), 2.34e2.83 (m, 7H), 2.98 (br t, J¼12.4 Hz, 0.6H,
equatorialeSCH2 of the major isomer), 3.14 (br t, J¼12.4 Hz, 0.6H,
equatorialeSCH2 of the major isomer), 3.20e3.39 (m, 0.8H, equa-
torialeSCH2 of the minor isomer), 3.90e4.03 (m, 1H, NCH2), 4.89
(br s, 0.4H, NCHS of the minor isomer), 5.18e5.25 (m, 0.6H, NCHS of
the major isomer), 5.34e5.44 (m, 0.6H, CHOBz of the major isomer),
5.48 (br s, 0.4H, CHOBz of the minor isomer), 6.98e7.10 (m, 2H),
7.28e7.45 (m, 4.4H), 7.46e7.62 (m, 1.6H), 7.83 (d, J¼6.8 Hz, 1.2H),
7.95 (d, J¼6.8 Hz, 0.8H); HRMS (EI) calcd for C27H35NO3S3Si
545.1543, found 545.1545.
4.13. (L)-(S)-3-Hydroxy-1-[2-(2-trimethylsilyl-1,3-dithian-2-
yl)ethyl]-2,6-piperidindione (37)
To a solution of 36 (631 mg, 1.82 mmol) in THF (5.5 mL) cooled
in a dry ice-acetone bath was added potassium tert-butoxide
(203 mg, 1.82 mmol) in one portion. The resulting mixture was
warmed up to ꢀ40 ꢁC over a period of 1.5 h and then quenched by
the addition of a saturated NH4Cl solution (10 mL). The resulting
mixture was poured into a mixture of brine and water (1:1) and
extracted with CH2Cl2. The combined organic layers were dried
(MgSO4), concentrated, and chromatographed on silica gel (he-
4.16. (6R/S,5S)-5-Benzoyloxy-1-[3-oxo-3-(trimethylsilyl)
propyl]-6-(phenylsulfenyl)piperidin-2-one (40)
xane/EtOAc, 4:6) to give 576 mg (91%) of 37 as a pale yellow solid:
21
[
a]
ꢀ23.4 (c 5.1, CHCl3); mp 110e111 ꢁC; IR (CH2Cl2) 3521 (br),
According to the general procedure for dithiane hydrolysis,
dithiane 39 (649 mg, 1.19 mmol) was hydrolyzed to give 433 mg
(80%) of 40 as a yellow liquid: IR (CH2Cl2) 1721, 1647 cmꢀ1; 1H NMR
D
1729, 1677 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d 0.24 (s, 9H, TMS),
1.80e1.97 (m, 2H), 1.99e2.08 (m, 1H), 2.26e2.40 (m, 3H), 2.43 (dt,
J¼14.0, 5.2 Hz, 2H, equatorialeSCH2), 2.63 (ddd, J¼18.2, 13.4,
5.2 Hz, 1H), 2.88 (ddd, J¼18.2, 4.6, 2.4 Hz, 1H), 3.07e3.18 (m, 2H,
axialeSCH2), 3.80e3.98 (m, 2H, NCH2), 4.21 (dd, J¼12.6, 5.4 Hz, 1H,
(CDCl3, 400 MHz)
d
ꢀ0.01 (s, 2.7H, TMS of the minor isomer), 0.20
(s, 6.3H, TMS of the major isomer), 2.05e2.17 (m,1H), 2.38e2.67 (m,
3H), 2.89e3.17 (m, 2H), 3.41e3.53 (m, 1H, NCH2), 3.78e3.90 (m, 1H,
NCH2), 5.28e5.36 (m, 1H, NCHS), 5.41 (br s, 0.3H, CHOBz of the
minor isomer), 5.43e5.47 (m, 0.7H, CHOBz of the major isomer),
7.06e7.17 (m, 2H), 7.26e7.41 (m, 3H), 7.46 (d, J¼8.0 Hz,1.3H), 7.51 (t,
J¼8.0 Hz, 1H), 7.58 (d, J¼6.8 Hz, 0.7H), 7.72 (d, J¼6.8 Hz, 1.4H), 7.90
(d, J¼6.8 Hz, 0.6H); HRMS (ESI) calcd for C24H29NNaO4SSi 478.1484,
found 478.1498.
CHO); 13C NMR (CDCl3, 100 MHz)
d
ꢀ2.3 (CH3), 23.5 (CH2), 25.3
(CH2), 25.7 (CH2), 31.1 (CH2), 33.6 (CH2), 37.0 (CH2), 39.6 (CH2),
68.3 (CH), 170.3 (C), 174.3 (C); HRMS (EI) calcd for C14H25NO3S2Si
347.1045, found 347.1049.
4.14. (6R/S,5S)-5-Hydroxy-1-[2-(2-trimethylsilyl-1,3-dithian-
2-yl)ethyl]-6-(phenylsulfenyl)piperidin-2-one (38)
4.17. (1R/S,8S,8aR)-8-Benzoyloxy-1-hydroxy-1,2,3,7,8,8a-
hexahydro-6H-indolizin-5-one (41)
To a solution of 37 (612 mg, 1.76 mmol) in 30 mL of a mixture of
MeOH/THF (7:1) cooled in a dry ice-CCl4 bath was added NaBH4
(333 mg, 8.8 mmol) in two portions separated by a period of 12 min.
The resulting mixture was stirred at the same temperature for
To a refluxing solution of 40 (67 mg, 0.15 mmol) in toluene
(1.5 mL) was added over 6 h using a syringe pump a solution of

M.-J. Chen, Y.-M. Tsai / Tetrahedron 67 (2011) 1564e1574
1571
tributyltin hydride (60
mL, 0.22 mmol) and ACCN (5 mg, 0.02 mmol)
4.20. (D)-(1R,2S,8S,8aS)-1,2-Diacetoxy-8-benzoyloxy-
in toluene (1.5 mL). The reaction mixture was heated for another
hour at the same temperature and then concentrated to give
a yellow liquid. The liquid was dissolved in THF (1.5 mL) followed by
the addition of a 1 M THF solution of TBAF (0.22 mL, 0.22 mmol).
The reaction mixture was stirred at rt for 35 min and then con-
centrated and chromatographed on slica gel (EtOAc/MeOH, 95:5) to
give 35 mg (86%) of 41 as a colorless oil: IR (CHCl3) 3466 (br), 1717
1,2,3,5,6,7,8,8a-octahydro-indolizine (43)
To a solution of 42 and its isomer (32.5 mg, 0.087 mmol) in THF
(1.7 mL) cooled in an ice-water bath was added borane dime-
thylsulfide complex (42 mL, 0.44 mmol). The resulting solution was
stirred at rt overnight and quenched by the addition of EtOH and
then concentrated in vacuo. The resulting residue was chromato-
(C]O), 1635 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
1.70e1.90 (m, 1H),
graphed on silica gel (hexane/EtOAc, 1:1) to give 25 mg (80%) of 43
20
1.94e2.08 (m, 1H), 2.10e2.28 (m, 2.4H), 2.42 (ddd, J¼17.4, 9.6,
6.4 Hz, 1H, COCH2), 2.47e2.63 (m, 1.3H), 3.38e3.63 (m, 3H),
3.65e3.76 (m, 0.3H), 4.14e4.24 (m, 1H), 5.06e5.17 (m, 1H, CHOBz),
7.39e7.49 (m, 2H), 7.53e7.62 (m, 1H), 8.01 (d, J¼7.2 Hz, 2H); HRMS
(ESI) calcd for C15H18NO4 (MþH)þ 276.1236, found 276.1226.
as a colorless oil: [
a
]
þ45.1 (c 2.5, CHCl3); IR (CH2Cl2) 1740,
D
1713 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
1.34 (qd, J¼11.2, 4.8 Hz, 1H,
C(7)H), 1.73e1.86 (m, 2H), 1.97 (td, J¼10.8, 3.4 Hz, 1H, C(5)H), 2.01
(s, 3H, COCH3), 2.03 (s, 3H, COCH3), 2.25e2.35 (m, 2H), 2.61 (dd,
J¼10.9, 7.2 Hz, 1H, C(3)H), 3.07 (br d, J¼10.8 Hz, 1H, C(5)H), 3.15 (dd,
J¼10.9, 1.8 Hz, 1H, C(3)H), 5.21 (ddd, J¼11.2, 9.6, 4.8 Hz, 1H, C(8)H),
5.26 (td, J¼7.2, 1.8 Hz, 1H, C(2)H), 5.49 (dd, J¼7.2, 4.6 Hz, 1H, C(1)H),
7.39 (t, J¼8.0 Hz, 2H), 7.52 (t, J¼8.0 Hz, 1H), 7.94 (d, J¼8.0 Hz, 2H);
4.18. (D)-(8S,8aR)-8-Benzoyloxy-3,7,8,8a-tetrahydro-6H-
indolizin-5-one (21)
13C NMR (CDCl3, 100 MHz)
d 20.5 (CH3), 20.8 (CH3), 23.4 (CH2), 30.0
(CH2), 51.9 (CH2), 59.5 (CH2), 68.9 (CH), 69.1 (CH), 70.0 (CH), 70.2
(CH), 128.2 (CH), 129.4 (CH), 129.9 (C), 132.8 (CH), 165.2 (C), 169.7
(C), 170.0 (C); HRMS (FAB) calcd for C19H24NO6 362.1604, found
362.1600.
To a solution of 41 (60 mg, 0.22 mmol) in THF (2.3 mL) cooled in
an ice-water bath was added over 20 min a solution of Martin
sulfurane (462 mg, 0.68 mmol) in Et2O (2.3 mL). The resulting so-
lution was stirred at rt overnight and then poured into a mixture of
brine and water, and extracted with CH2Cl2. The organic layer was
dried (MgSO4), concentrated, and chromatographed on silica gel
4.21. (D)-Swainsonine (ent-9)
(hexane/EtOAc, 2:8) to give 41 mg (73%) of 21 as a pale yellow solid:
To a solution of 43 (21 mg, 0.058 mmol) in MeOH (1 mL) was
added NaOH (16 mg, 0.40 mmol). The resulting mixture was stirred
at rt for 1 h and then directly chromatographed on Dowex-50Wꢂ8
21
[
a]
þ71.6 (c 5.2, CHCl3); mp 77e78 ꢁC; IR (CHCl3) 1720, 1646,
D
1617 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
1.99 (dq, J¼13.2, 8.2 Hz,1H),
2.34 (dq, J¼13.2, 5.8 Hz, 1H), 2.55 (dt, J¼17.4, 8.0 Hz, 1H, COCH2),
2.67 (ddd, J¼17.4, 8.0, 5.4 Hz, 1H, COCH2), 4.10 (dd, J¼17.6, 4.8 Hz,
1H, NCH2), 4.46e4.56 (m, 2H), 4.96 (td, J¼8.2, 5.8 Hz, 1H, CHOBz),
5.88e5.99 (m, 2H, HC]CH), 7.45 (t, J¼7.6 Hz, 2H), 7.58 (t, J¼7.6 Hz,
resin (eluted with MeOH followed by aqueous NH4OH) to give ent-9
24
as a white soild: [
a
]
D
þ80.6 (c 0.3, MeOH); mp 138e140 ꢁC [lit.46
25
[a
]
þ75 (c 0.92, MeOH); mp 142e143 ꢁC]. The NMR-spectro-
D
scopic analysis is consistent with literature data.46
1H), 8.03 (d, J¼7.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d 27.0 (CH2),
29.8 (CH2), 53.1 (CH2), 66.4 (CH), 72.0 (CH), 126.9 (CH), 127.1 (CH),
128.0 (CH), 129.1 (C), 129.2 (CH), 132.9 (CH), 164.8 (C), 167.7 (C);
HRMS (ESI) calcd for C15H16NO3 (MþH)þ 258.1130, found 258.1121.
4.22. 2-(3-Aminopropyl)-2-diphenylmethylsilyl-1,3-dithiane
(45)
Using the same procedure as the synthesis of amine 19, dithiane
44 (11.7 g, 36.9 mmol) was alkylated with bromide 26 (8.70 g,
38.5 mmol) to give 12.7 g (91%) of 4ꢀ51as a pale yellow solid: mp
4.19. (1R,2S,8S,8aS)-1,2-Diacetoxy-8-benzoyloxy-1,2,3,7,8,8a-
hexahydro-6H-indolizin-5-one (42)
70e71 ꢁC; IR (CH2Cl2) 3072, 3047 cm
;
1H NMR (C6D6, 400 MHz)
d0.90 (s, 3H), 1.04 (br s, 2H, NH2), 1.35e1.46 (m, 1H), 1.54e1.65 (m,
A solution of 21 (43 mg, 0.17 mmol) and NMO (39 mg, 0.34 mmol)
in 1.7 mL ofa mixed solventof acetone/water(1:0.7) wascooled in an
ice-water bath. To it was added osmium tetroxide (26.6 mg,
0.105 mmol), and the reaction mixture was stirred at the same
temperature for 2 h and then quenched by the addition of NaHSO3
(118 mg). The resulting mixture was diluted with EtOAc, dried
(MgSO4), filtered, and concentrated. Theresulting residual oil, DMAP
3H), 2.04 (ddd, J¼14.4, 4.8, 3.6 Hz, 2H, equatorialeSCH2), 2.24e2.35
(m overlapped with t at 2.33, J¼6.8 Hz, 4H), 2.69 (ddd, J¼14.4, 11.6,
2.8 Hz, 2H, axialeSCH2), 7.16e7.27 (m, 6H), 7.98e8.06 (m, 4H); 13
C
NMR (C6D6, 100 MHz)
d
ꢀ2.0 (CH3), 25.1 (CH2), 26.0 (CH2), 32.4
(CH2), 36.6 (CH2), 40.5 (s), 43.4 (CH2), 128.3 (CH), 130.2 (CH), 135.4
(C), 136.8 (CH); HRMS (EI) calcd for C20H27NS2Si 373.1349, found
373.1352.
(6 mg, 0.05 mmol) and Et3N (93
CH2Cl2 (1.5 mL) and then cooled in an ice-water bath. To the solution
was added slowly acetic anhydride (47 L, 0.50 mmol), and the
mL, 0.67 mmol) were dissolved in
4.23. (L)-(S)-N-[3-(2-Diphenylmethylsilyl-1,3-dithian-2-yl)
propyl]-tetrahydro-5-oxo-2-furancarboxamide (46)
m
resulting mixture was stirred at rt for 5 h and concentrated to give
a liquid. The liquid was chromatographed on silica gel (EtOAc) to
afford 34.5 mg (55%) of 42 and its (1S,2R) isomer (10:1) as a mixture.
Major isomer 42: IR (CH2Cl2) 1752,1725,1650 cmꢀ1; 1H NMR (CDCl3,
To a solution of acid 23 (2.40 g, 18.5 mmol) and a few drops of
DMF in CH2Cl2 (40 mL) cooled in an ice-water bath was added over
15 min oxalyl chloride (1.90 mL, 22.3 mmol). The reaction mixture
was stirred at rt overnight and then concentrated to give a liquid.
The liquid and Et3N (3.20 mL, 23.1 mmol) were dissolved in THF
(20 mL) and cooled in an ice-water bath. To the solution was added
over 40 min a solution of 43 (5.75 g, 23.1 mmol) in THF (25 mL). The
resulting mixture was stirred at rt for 3 h and then partitioned
between water and CH2Cl2. The organic layer was dried (MgSO4),
400 MHz) d 1.94e2.09 (m overlapped with s at 2.02, 4H), 2.11 (s, 3H,
COCH3), 2.29e2.35 (m, 1H), 2.49e2.67 (m, 2H, COCH2), 3.57 (dd,
J¼12.0, 8.8 Hz, 1H, C(3)H), 3.85 (dd, J¼12.0, 8.8 Hz, 1H, C(3)H), 3.94
(dd, J¼9.0, 3.6 Hz,1H, C(8a)H), 5.30 (ddd, J¼10.4, 9.0, 3.4 Hz,1H, C(8)
H), 5.36 (td, J¼8.8, 3.6 Hz, 1H, C(2)H), 5.44 (t, J¼3.6 Hz, 1H, C(1)H),
7.43 (t, J¼7.6 Hz, 2H), 7.57 (t, J¼7.6 Hz,1H), 7.95 (d, J¼7.6 Hz, 2H); 13C
NMR (CDCl3, 100 MHz)
d
20.5 (CH3), 20.6 (CH3), 26.6 (CH2), 29.3
concentrated, and chromatographed on silica gel (hexane/EtOAc,
23
(CH2), 46.5 (CH2), 62.4 (CH), 66.1 (CH), 69.2 (CH), 70.3 (CH), 128.3
(CH), 129.0 (C), 129.5 (CH), 133.3 (CH), 165.0 (C), 167.8 (C), 169.4 (C),
169.8 (C); HRMS (ESI) calcd for C19H21NNaO7 398.1216, found
398.1239.
2:8) to give 4.94 g (66%) of 46 as a pale yellow solid: [
a
]
D
ꢀ7.0 (c
3.3, CHCl3); mp 42e43 ꢁC; IR (CH2Cl2) 3430, 1790, 1710, 1679 cmꢀ1
1H NMR (CDCl3, 400 MHz)
0.77 (s, 3H), 1.53e1.62 (m, 2H),
1.82e2.02 (m, 2H), 2.12e2.20 (m, 2H), 2.21e2.30 (m, 1H), 2.43 (dt,
;
d

1572
M.-J. Chen, Y.-M. Tsai / Tetrahedron 67 (2011) 1564e1574
J¼14.0, 4.0 Hz, 2H, equatorialeSCH2), 2.46e2.62 (m, 3H), 2.94 (br t,
J¼14.0 Hz, 2H, axialeSCH2), 3.03e3.20 (m, 2H, NCH2), 4.73 (t,
J¼7.4 Hz, 1H, CHO), 6.16 (br s, 1H, NH), 7.32e7.44 (m, 6H), 7.78 (d,
3H), 7.25e7.44 (m, 9H), 7.45e7.50 (m,1H), 7.55 (t, J¼7.4 Hz,1H), 7.65
(d, J¼6.8 Hz, 2H), 7.74e7.83 (m, 3H), 7.94 (d, J¼7.2 Hz, 1H). Anal.
Calcd for C38H41NO3S3Si: C, 66.72; H, 6.04; N, 2.05; S, 14.06. Found:
C, 66.44; H, 6.20; N, 1.88; S, 13.69.
J¼6.4 Hz, 4H); 13C NMR (CDCl3, 100 MHz)
d
ꢀ3.4 (CH3), 24.4 (CH2),
24.9 (CH2), 26.1 (CH2), 27.6 (CH2), 27.9 (CH2), 35.3 (CH2), 38.8 (C),
39.5 (CH2), 77.2 (CH), 127.3 (CH), 129.4 (CH), 133.5 (C), 135.4 (CH),
168.3 (C), 174.9 (C); HRMS (EI) calcd for C25H31NO3S2Si 485.1509,
found 485.1511.
4.27. (6R/S,5S)-5-Benzoyloxy-1-[4-oxo-4-
(diphenylmethylsilyl)butyl]-6-(phenylsulfenyl)piperidin-2-
one (51)
4.24. (L)-(S)-3-Hydroxy-1-[3-(2-diphenylmethylsilyl-1,3-
According to the general procedure for dithiane hydrolysis,
dithian-2-yl)propyl]-2,6-piperidindione (47)
dithiane 50 (1.40 g, 2.05 mmol) was hydrolyzed to give 1.11 g (91%)
of 51 as a yellow liquid: IR (CH2Cl2) 1721, 1650 cmꢀ1 1H NMR
;
Using the same procedure as the synthesis of imide 37, lactone
amide 46 (2.74 g, 5.63 mmol) was rearranged to give 2.43 g (89%) of
(CDCl3, 400 MHz) d 0.69 (s, 0.9H, SiCH3 of the minor isomer), 0.77 (s,
2.1H, SiCH3 of the major isomer), 1.80 (quintet, J¼7.0 Hz, 2H),
1.99e2.14 (m, 1H), 2.14e2.78 (m, 5H), 3.03 (dt, J¼13.8, 7.2 Hz, 1H,
NCH2), 3.88 (dt, J¼13.8, 7.2 Hz, 1H, NCH2), 4.84 (s, 0.3H, NCHS of the
minor isomer), 5.19e5.21 (m, 0.7H, NCHS of major isomer), 5.30 (dt,
J¼10.8, 4.0 Hz, 0.7H, CHOBz of the major isomer), 5.43 (s, 0.3H,
CHOBz of the minor isomer), 7.02e7.11 (m, 2.3H), 7.31e7.46 (m,
10H), 7.48e7.64 (m, 5.7H), 7.76 (d, J¼7.6 Hz, 1.4H), 7.88 (d, J¼7.2 Hz,
0.6H); HRMS (ESI) calcd for C35H36NO4SSi (MþH)þ 594.2134, found
594.2178.
47 as a pale yellow solid: [
a
]
23 ꢀ18.8 (c 1.1, CHCl3); mp 114e115 ꢁC;
D
IR (CH2Cl2) 3509 (br), 1678 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d
0.78
(s, 3H), 1.60e1.76 (m, 3H), 1.82e2.04 (m, 3H), 2.05e2.16 (m, 2H),
2.19e2.27 (m, 1H), 2.38e2.45 (m overlapped with br d, J¼14.0 Hz,
3H), 2.74 (ddd, J¼15.6, 4.4, 2.0 Hz, 1H), 2.99 (br t, J¼14.0 Hz, 2H,
axialeSCH2), 3.59e3.72 (m, 2H, NCH2), 3.97 (dd, J¼13.0, 5.4 Hz, 1H,
CHO), 7.31e7.44 (m, 6H), 7.77 (d, J¼8.4 Hz, 4H); 13C NMR (CDCl3,
100 MHz)
d
ꢀ3.3 (CH3), 24.3 (CH2), 25.0 (CH2), 25.6 (CH2), 26.2
(CH2), 31.1 (CH2), 35.0 (CH2), 38.8 (C), 40.5 (CH2), 68.1 (CH), 127.2
(CH),129.3 (CH),133.5 (C), 135.4 (CH),170.2 (C), 174.3 (C); HRMS (EI)
calcd for C25H31NO3S2Si 485.1509, found 485.1513.
4.28. (1S,9R/S,9aS)-1-Benzoyloxy-9-diphenylmethylsilyloxy-
1,2,3,6,7,8,9,9a-octahydro-4H-quinolizin-4-one (52) and (L)-
(S)-5-benzoyloxy-1-[4-oxo-4-(diphenylmethylsilyl)butyl]
piperidin-2-one (53)
4.25. (6R/S,5S)-5-Hydroxy-1-[3-(2-diphenylmethylsilyl-1,3-
dithian-2-yl)propyl]-6-(phenylsulfenyl)piperidin-2-one (48)
and (3S,6R/S)-3-hydroxy-1-[3-(2-diphenylmethylsilyl-1,3-
dithian-2-yl)propyl]-6-(phenylsulfenyl)piperidin-2-one (49)
To a refluxing solution of 51 (471 mg, 0.794 mmol) in toluene
(7.9 mL) was added over 6 h using a syringe pump a solution of
TBTH (0.32 mL, 1.2 mmol) and ACCN (29 mg, 0.12 mmol) in toluene
(1.5 mL). The reaction mixture was heated for another hour at the
same temperature and then concentrated and chromatographed on
silica gel (hexane/EtOAc/Et3N, 40:60:1) to give 297 mg (77%) of 52
(exo/endo¼1.3) as a pale yellow liquid, and 34 mg (9%) of 53 as
Using the same procedure as the synthesis of sulfide 38, imide
47 (2.27 g, 4.67 mmol) was reduced and exchanged to give 2.14 g
(79%) of 48 as a colorless oil: IR (CHCl3) 3596 (br), 1650 cmꢀ1 1H
;
NMR (CDCl3, 400 MHz)
d 0.67 (s, 1.8H, SiCH3 of the major isomer),
0.74 (s, 1.2H, SiCH3 of the minor isomer), 1.47 (quintet, J¼7.6 Hz,
1.6H), 1.65e2.01 (m, 4H), 2.02e2.55 (m, 7.4H), 2.82e3.04 (m, 3H),
3.73 (br s, 0.6H), 3.94e4.14 (m, 1.8H), 4.37 (dd, J¼4.4, 2 Hz, 0.6H,
NCHS of the major isomer), 7.24e7.45 (m, 11H), 7.68e7.80 (m, 4H);
HRMS (EI) calcd for C31H37NO2S3Si 579.1750, found 579.1725. We
also isolated 119 mg (4%) of 49 as a colorless oil: IR (CHCl3) 3501
a colorless liquid. Compound 52: IR (CH2Cl2) 1719,1638 cmꢀ1 1H
;
NMR (CDCl3, 400 MHz) d 0.69 (s, 1.35H, SiCH3 of endo isomer), 0.72
(s, 1.65H, SiCH3 of exo isomer), 1.31e2.00 (m, 4.9H), 2.08 (br d,
J¼10.4 Hz, 0.55H), 2.23 (dd, J¼17.6, 5.6 Hz, 0.55H), 2.28e2.61 (m,
3H), 3.39e3.50 (m, 1.55H), 4.17 (br s, 0.45H, C(8)H of endo isomer),
4.70 (br d, J¼12.8 Hz, 0.55H, NCH2 of exo isomer), 4.83 (br d,
J¼13.2 Hz, 0.45H, NCH2 of endo isomer), 5.18 (dt, J¼6.8, 3.6 Hz,
0.45H, CHOBz of endo isomer), 5.78 (br s, 0.55H, CHOBz of exo
isomer), 7.29e7.46 (m, 8H), 7.51e7.59 (m, 3H), 7.61 (d, J¼6.0 Hz,
1.1H), 7.66 (d, J¼6.0 Hz, 0.9H), 7.96 (d, J¼7.2 Hz, 0.9H), 8.01 (d,
(br), 1647 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d 0.75 (s, 2.1H, SiCH3 of
the major isomer), 0.77 (s, 0.9H, SiCH3 of the minor isomer),
1.36e2.23 (m, 11H), 2.36e2.48 (m, 2H, equatorialeSCH2), 2.96 (br t,
J¼11.4 Hz, 2H, axialeSCH2), 2.99e3.17 (m, 1H, NCH2), 3.64 (dd,
J¼10.0, 6.0 Hz, 0.3H, CHO of the minor isomer), 3.81 (dd, J¼11.4,
6.8 Hz, 0.7H, CHO of the major isomer), 3.89 (dt, J¼13.6, 6.8 Hz,
0.3H, NCH2 of the minor isomer), 4.01 (dt, J¼13.6, 6.8 Hz, 0.7H,
NCH2 of the major isomer), 4.11 (t, J¼6.8 Hz, 0.3H, NCHS of the
minor isomer), 4.23 (br s, 0.7H, NCHS of the major isomer),
7.25e7.43 (m, 11H), 7.74 (d, J¼7.6 Hz, 2.8H), 7.78 (d, J¼7.6 Hz, 1.2H);
HRMS (ESI) calcd for C31H37NNaO2S3Si (MþNa)þ 602.1653, found
602.1652.
J¼7.2 Hz, 1.1H); HRMS (FAB) calcd for C29H32NO4Si (MþH)þ
19
486.2101, found 486.2096. 53: [
a]
ꢀ8.2 (c 5.8, CHCl3); IR (CHCl3)
D
1717, 1636 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d 0.74 (s, 3H, SiCH3),
1.60e1.82 (m, 2H), 1.96e2.15 (m, 2H), 2.36 (dt, J¼17.2, 5.2 Hz, 1H),
2.55 (ddd, J¼17.2, 10.4, 6.8 Hz, 1H), 2.60e2.79 (m, 2H), 3.18e3.35
(m, 2H, exocycliceNCH2), 3.39 (dd, J¼13.2, 2.6 Hz, 1H, C(6)H), 3.58
(dd, J¼13.2, 4.0 Hz, 1H, C(6)H), 5.36 (br s, 1H, CHOBz), 7.26e7.46 (m,
9H), 7.54 (d, J¼6.8 Hz, 4H), 7.96 (d, J¼7.2 Hz, 2H); 13C NMR (CDCl3,
100 MHz)
d
ꢀ5.2 (CH3), 19.2 (CH2), 25.6 (CH2), 27.9 (CH2), 46.3
4.26. (6R/S,5S)-5-Benzoyloxy-1-[3-(2-diphenylmethylsilyl-1,3-
dithian-2-yl)propyl]-6-(phenylsulfenyl)piperidin-2-one (50)
(CH2), 46.6 (CH2), 51.2 (CH2), 66.7 (CH), 128.0 (CH), 128.3 (CH), 129.4
(CH), 129.9 (CH), 132.1 (C), 132.2 (C), 133.1 (CH), 134.7 (CH), 165.3
(C), 168.3 (C), 242.7 (C); HRMS (ESI) calcd for C29H31NNaO4Si
(MþNa)þ 508.1920, found 508.1928.
Using the same procedure as the synthesis of benzoate 39, al-
cohol 48 (2.10 g, 3.46 mmol) was esterified to give 2.18 g (92%) of 50
as a colorless oil: IR (CH2Cl2) 1720, 1651 cmꢀ1
;
1H NMR (CDCl3,
4.29. (L)-(1S,9R,9aR)-1-Benzoyloxy-9-hydroxy-
1,2,3,6,7,8,9,9a-octahydro-4H-quinolizin-4-one (54a) and (L)-
(1S,9S,9aR)-1-benzoyloxy-9-hydroxy-1,2,3,6,7,8,9,9a-
octahydro-4H-quinolizin-4-one (54b)
400 MHz) d 0.52 (s, 1.65H, SiCH3 of the major isomer), 0.76 (s, 1.35H,
SiCH3 of the minor isomer), 1.38e1.54 (m, 0.55H), 1.55e2.12 (m,
5.45H), 2.13e2.63 (m, 6H), 2.77e3.03 (m, 3H), 3.86e3.98 (m, 1H),
4.52 (br s, 0.55H, NCHS of the major isomer), 4.82 (br s, 0.45H, NCHS
of the minor isomer), 5.11e5.19 (m, 0.45H, CHOBz of the minor
isomer), 5.43 (s, 0.55H, CHOBz of the major isomer), 7.12e7.23 (m,
A solution of 52 (297 mg, 0.611 mmol) and p-toluenesulfonic
acid monohydrate (11 mg, 0.058 mmol) in MeOH (6 mL) was stirred

M.-J. Chen, Y.-M. Tsai / Tetrahedron 67 (2011) 1564e1574
1573
23
20
at rt for 1 h and then quenched by the addition of a few drops of
Et3N. The reaction mixture was concentrated and chromato-
graphed on silica gel (eluted with EtOAc followed by EtOAc/MeOH,
95:5) to give 177 mg (100%) of a mixture of 54a/b (1.3:1). The
presence of 54a was confirmed by comparison of the 1H NMR data
of the mixture with that reported in the literature.39
[a
]
ꢀ10.3 (c 1.1, CHCl3) [lit.41
[a
]
ꢀ8.5 (c 0.7, CHCl3)]; mp
D
D
71e72 ꢁC. The NMR-spectroscopic analysis is consistent with lit-
erature data.
Acknowledgements
To a solution of 54a/b (135 mg, 0.467 mmol) in CH2Cl2 (5 mL) at
rt was added slowly a 0.5 M solution of DesseMartin periodinane in
CH2Cl2. The reaction mixture was stirred for another 2 h and then
partitioned between saturated NaHCO3 solution and CH2Cl2. The
organic layer was washed with a saturated Na2S2O3 solution, dried
(MgSO4), and concentrated to give a liquid. The liquid was chro-
matographed on silica gel (hexane/EtOAc, 2:8) to give 114 mg of
a ketone. To a solution of the ketone in THF (1.2 mL) cooled in a dry
ice-acetone bath was added a 1 M solution of L-Selectride in THF
(0.14 mL, 0.14 mmol). The reaction mixture was stirred at the same
temperature for another 40 min, quenched by the addition of brine
at low temperature and then slowly warmed up to rt. The resulting
mixture was extracted with EtOAc. The organic layer was dried
(MgSO4), concentrated, and chromatographed on silica gel (EtOAc)
We thank the National Science Council of the Republic of China
for financial support.
Supplementary data
Additional experimental procedures and compound character-
ization data of the trimethylsilyl analogs of compounds shown in
Scheme 6. 1H/13C NMR spectra of 14, 17, 19, 21, 27e55. Supple-
mentary data related to this article can be found online at
doi:10.1016/j.tet.2010.12.048. These data include MOL files and
InChiKeys of the most important compounds described in this
article.
to give 23 mg (55%) of 54b as a white solid: [
a
]
23 ꢀ7.7 (c 2.5, CHCl3);
References and notes
D
mp 112e113 ꢁC; IR (CH2Cl2) 3450 (br), 1714,1632 cmꢀ1
;
1H NMR
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1.53 (br d, J¼12.8 Hz, 1H, C(7)H), 1.67 (br t,
€
New York, NY, 1995; (b) Giese, B.; Kopping, B.; Gobel, T.; Dickhaut, J.; Thoma, G.;
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(2)H, C(8)H), 2.34e2.68 (m, 5H), 3.45 (d, J¼4.0 Hz, 1H, NCH), 4.03
(br s, 1H, C(9)H), 4.77 (dt, J¼13.6, 2.0 Hz, 1H, C(6)H), 5.42 (dt, J¼7.2,
4.0 Hz, 1H, CHOBz), 7.43 (t, J¼7.6 Hz, 2H), 7.57 (t, J¼7.6 Hz, 1H), 8.00
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(d, J¼7.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
d 19.3 (CH2), 24.9
(CH2), 28.6 (CH2), 32.1 (CH2), 42.9 (CH2), 64.0 (CH), 65.8 (CH), 70.0
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4H-quinolizin-4-one (55)
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a
]
21 ꢀ12.3 (c 2.4, CHCl3);
D
IR (CHCl3) 1716, 1628 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d 1.15e1.60
(m, 3H), 1.66 (br d, J¼13.2 Hz, 1H), 1.89 (br t, J¼13.2 Hz, 2H),
1.99e2.18 (m, 2H), 2.38e2.45 (m, 2H), 2.64 (ddd, J¼13.6, 10.8,
6.0 Hz,1H), 3.45 (br d, J¼12.0 Hz,1H, NCH), 4.77 (br d, J¼13.6 Hz,1H,
NCH2), 5.10 (dt, J¼5.2, 2.6 Hz,1H, CHOBz), 7.41 (t, J¼8.0 Hz, 2H), 7.54
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23.5 (CH2), 24.9 (CH2), 25.5 (CH2), 28.1 (CH2), 31.5 (CH2), 43.4
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1574
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