Stereoselective synthesis of (-)-8-epi-swainsonine starting with a chiral aziridine

Article abstract of DOI:10.1016/j.tetlet.2012.11.087

An efficient synthesis of (-)-8-epi-swainsonine, starting from a commercially available 1-(R)-α-methylbenzylaziridine-2-methanol, was developed. The synthetic route utilizes stereocontrolled Sharpless asymmetric dihydroxylation governed by AD-mix-β followed by an aziridine ring opening-cyclization sequence to generate the five membered N-heterocyclic ring system present in the bicyclic target. A subsequent stereoselective allylation and piperidine ring forming cyclization then produced a precursor that was converted into (-)-8-epi-swainsonine.

Full text of DOI:10.1016/j.tetlet.2012.11.087

Tetrahedron Letters 54 (2013) 553–556
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of (À)-8-epi-swainsonine starting
with a chiral aziridine
Baeck Kyoung Lee a, Hwan Geun Choi a, Eun Joo Roh a, Won Koo Lee b, Taebo Sim a,
⇑
a Future Convergence Research Division, Korea Institute of Science and Technology, P.O. Box 131,Cheongryang, Seoul 130-650, Republic of Korea
b Department of Chemistry, Sogang University, Seoul 121-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of (À)-8-epi-swainsonine, starting from a commercially available 1-(R)-
a-methylb-
Received 17 August 2012
Revised 13 November 2012
Accepted 21 November 2012
Available online 7 December 2012
enzylaziridine-2-methanol, was developed. The synthetic route utilizes stereocontrolled Sharpless asym-
metric dihydroxylation governed by AD-mix-b followed by an aziridine ring opening-cyclization
sequence to generate the five membered N-heterocyclic ring system present in the bicyclic target. A sub-
sequent stereoselective allylation and piperidine ring forming cyclization then produced a precursor that
was converted into (À)-8-epi-swainsonine.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Indolizidine alkaloids
(À)-8-Epi-swainsonine
Total synthesis
Aziridine
Natural product
Polyhydroxylated indolizidine alkaloids, such as (+)-castano-
spermine (1), (+)-lentiginosine (2), and (À)-swainsonine (3) in
Figure 1, have received great attention owing to their interesting
biological properties.1 For example, (+)-castanospermine2 (1) is
known to have antiviral activity and (+)-lentiginosine3 (2) is an
amyloglucosidase inhibitor. (À)-Swainsonine (3), first isolated
from the fungus Rhizoctonia leguminicola,4 displays potent activi-
whereas its enantiomer is not an inhibitor of this enzyme.14 Sev-
eral groups have described the syntheses of (À)-8-epi-swainsonine
(4) that rely on stereoselective addition of allenes to chiral sulfinyl-
imine,15 aza-pinacol rearrangements of polyhydroxylated pyrrol-
idines,16 nitrone cycloaddition to pyrrolo[1,2-a]azepine,17a RCM
using Grubbs catalyst,13b,17 and stereoselective dihydroxylations
of
a
,b-unsaturated lactams.18
In recent studies, described below, we have developed an effi-
ties against lysosomal
a-D
-mannosidase5 and Golgi mannosidase
II.6 Moreover, this indolizidine alkaloid possesses anti-proliferative
activity7 and, as a result, it has been subjected to clinical investiga-
tion for the treatment of cancer.8 It has also been reported9 that
(À)-swainsonine stimulates bone marrow cell proliferation and
differentiation.
cient and stereoselective synthesis of (À)-8-epi-swainsonine,
which begins with a commercially available chiral aziridine that
HO
HO
Owing to these interesting biological and pharmacological
properties, various routes1c,10 for the synthesis of (À)-swainsonine
and its analogs have been developed since the time of its first prep-
aration in 1984.11
N
N
HO
As exemplified by those devised by Richardson11d and Fleet,11a
most of the approaches employ carbohydrate starting materials
as chirality sources. Additional efforts in this area have focused
on the preparation of stereoisomers of (À)-swainsonine, including
(+)-swainsonine12 and (À)-8-epi-swainsonine,13 with the aim of
obtaining more highly bioactive substances. Interestingly, the
(+)-swainsonine was found to be a selective and potent inhibitor
H
H
HO
HO
OH
(+)-castanospermine (1)
(+)-lentiginosine (2)
N
N
HO
H
HO
H
of naringinase (L-rhamnosidase) with a Ki value of 0.45 lM,
HO
OH
HO
OH
(–)-swainsonine (3)
(–)-8-epi-swainsonine (4)
⇑
Corresponding author. Tel.: +82 2 958 6347; fax: +82 2 958 5189.
E-mail address: tbsim@kist.re.kr (T. Sim).
Figure 1. Indolizidine alkaloids’ analogs.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.087

554
B. K. Lee et al. / Tetrahedron Letters 54 (2013) 553–556
Ph
O
Ph
Brown
allylation
H
O
intramolecular
cyclization
N
N
N
O
O
HO
HO
O
H
HO
OH
O
O
4
5a
6
(–)-8-epi-swainsonine ( )
Sharpless
asymmetric
dihydroxylation
Ph
Ph
Ph
acid-catalyzed aziridine ring
cleavage and cyclization
OH
N
N
H
N
CO2Me
OH
H
H
OH
CO2Me
7a
8
9
Scheme 1. Retrosynthetic analysis used to design the synthesis of (À)-8-epi-swainsonine (4).
until now has not been used as a starting material for the synthesis
of this target.
1H NMR analysis), whereas the process carried out at 5 °C is extre-
mely sluggish (7 days) but it occurs with a higher level of diastere-
oselectivity (7a:7b = 20:1). Importantly, subjection of the mixture
formed in the room temperature reaction to flash column chroma-
tography provided 7a as a single diastereomer in 70% yield. Finally,
the stereochemical assignment of 7a rests on its conversion to the
pyrrolidinone-2-one acetonide 12 (see below).
Further studies of the dihydroxylation reaction of the N-(R)-1-
phenylethyl-protected (Z)-enoate 8 showed that treatment with
osmium tetraoxide in the absence of (DHQD)2PHAL leads to non-
stereoselective (1:1 dr) production of a mixture of 7a and 7b. It
is noteworthy that (Z)-2-alkenyl-1-[(R)-1-phenylethyl]aziridines19
and (E)-3-(aziridin-2-yl)acrylates,20 N-protected with carbamate
groups (ethyl or tert-butyl), have been found to undergo stereose-
lective (ca., 9:1 dr) dihydroxylation when reacted with osmium
tetroxide alone and that N-unprotected (E)-3-(aziridin-2-yl)acry-
lates20 undergo non-stereoselective (1:1 dr) osmium tetroxide pro-
moted dihydroxylations.
In continuing efforts aimed at the synthesis of (À)-8-
epi-swainsonine, we observed that regioselective aziridine ring-
opening21 of aziridine-diol 7a takes place when it is treated with
acetic acid in CH2Cl2 and that the crude product of this process is
directly transformed to pyrrolidinone 11 (82% yield, 2 steps) when
heated in toluene at 90 °C (Scheme 3).
Acetonide protection of the diol in 11 occurs smoothly to afford
12 (88%). The relative C4 and C5 stereochemistry in pyrrolidinone-
2-one 12 and, consequently, that of diol 7a was determined by
using 1H NMR spectroscopy and NOESY experiments. The coupling
constants between cis protons at C4 and C5 of the pyrrolidinone-
The plan we devised is outlined in a retrosynthetic manner in
Scheme 1. In the route, the bicyclic indolizidine ring system of
the target is prepared by piperidine ring forming cyclization of
5a, which is produced from pyrrolidinone 6 by using an asymmet-
ric Brown allylation process. In addition, we hypothesized that 6
would be formed from aziridine 7a by employing a sequence
involving acid-catalyzed aziridine ring-opening and subsequent
pyrrolidinone ring forming cyclization. Finally, a Sharpless asym-
metric dihydroxylation of the aziridine-acrylate 8, arising from a
commercially available 1-(R)-a-methylbenzylaziridine-2-metha-
nol 9, would be utilized to generate 7a.
Studies aimed at the synthesis of (À)-8-epi-swainsonine com-
menced with Swern oxidation of 1-(R)-a-methylbenzylaziridine-
2-methanol 9 that generates the corresponding aldehyde 10
(Scheme 2). Wittig olefination of 10 with carbomethoxymethyl-
ene-triphenylphosphorane afforded the desired aziridine-acrylate
as a 4:1 mixture of (Z)- and (E)-isomers, which are readily sepa-
rated by using column chromatography to afford (Z)-enoate 8 in
62% yield. It has been reported that (Z)-enoates bearing C-4 chiral
centers undergo AD-mix-b promoted dihydroxylations to produce
(2S,3R)-2,3-dihydroxyester independent of the configuration at
the C4 center. Based on this precedent, (Z)-enoate 8 was subjected
to Sharpless asymmetric dihydroxylation using AD-mix-b. Impor-
tantly, although requiring a long time period (1 day), this process
resulted in highly diastereoselective formation of the (2S,3R)-2,3-
dihydroxyester 7a. Accordingly, the dihydroxylation reaction per-
formed at room temperature gives 7a and 7b in a 10:1 ratio (by
Ph
Ph
Ph
Ph3P=CHCO2Me
(R)
(R)
N
Swern Oxdation
N
(1.2 equiv)
N
(R)
( R)
O
OH
H
8
MeOH, 0 °C
62% (2 steps) for
(Z/E = 4:1)
CO2Me
9
10
8
Ph
Ph
AD-mix-β
CH3SO2NH2 (1.5 equiv)
OH
OH
+
N
N
CO2Me
CO2Me
H
H
t-BuOH:H2O (1:1)
OH
7a
OH
7b
70%
7a / 7b = 10 / 1 (rt),
20 / 1 (5 °C)
Scheme 2. Route for the preparation of 7a.

B. K. Lee et al. / Tetrahedron Letters 54 (2013) 553–556
555
Ph
Ph
MeO
OMe
1. AcOH (10 equiv) ,
OH
N
TsOH.H2O (0.1 equiv)
DCM, RT, 1 h, 88%
DCM, RT
O
N
CO2Me
AcO
HO
2. Tol , 90 oC, 12 h, 82%
H
OH
7a
HO
OH 11
Ph
O
Ph
N
Dess-Martin periodinane
(1.5 equiv)
N
5
O
O
KOH (2 equiv)
AcO
4
MeOH, RT, 1 h, 86%
O
DCM, RT, 3 h
O
O
12
13
Ph
Ph
O
Ph
(-)-Ipc2BOMe (3 equiv),
allylMgBr (3 equiv),
H
O
H
N
N
N
O
O
O
+
HO
HO
O
ether/DCM, -78 oC to 0 oC, 3 h
2 step yield 63%,
O
O
O
O
6
5b
5a
5a / 5b = 4 / 1
Scheme 3. Synthesis of 5a.
2-ones are known to be larger than those of the corresponding
trans protons (Jcis = 3.7-4.2 Hz, Jtrans = 0 Hz).22 The observation that
J4,5 = 5.0 and 3.4 Hz for 11 and 12, respectively, clearly demon-
strates that these substances possess cis C4–C5 stereochemistry
and, as a result, the absolute configuration of C4 is S in both 11
and 12. Lastly, base promoted hydrolysis of the acetate group in
12 furnishes the corresponding primary alcohol 13 in 86% yield.
Primary alcohol 13 was converted by Dess–Martin periodinane
oxidation for 3 h into the corresponding aldehyde 6, which in its
crude form was subjected to asymmetric Brown allylation23 to
install the homoallylic alcohol side chain containing the final
stereogenic center of the polyhydroxylated-indolizidine target.
Reaction of 6 with (À)-Ipc2BOCH3 and allylmagnesium bromide
at À78 °C gives the desired adduct in 63% yield with a moderate le-
vel of diastereoselectivity (5a:5b = 4:1). Isomer 5a, needed in the
synthetic route, was acquired in diastereomerically pure form by
using column chromatography (63% yield, 2 steps). It is worth not-
ing that Brown allylation of 6 using (+)-Ipc2BOCH3, carried out in
order to form 5b as a potential intermediate for (À)-swainsonine
synthesis, results in the formation of an unknown substance.
As described in Scheme 4, protection of the allylic alcohol 5a
with TBSOTf gives TBS-ether 14 (99%), which is treated with the
HO
TBSOTf (1.5 equiv),
2,6-Lutidine (2 equiv)
Ph
O
Ph
O
BH3DMS (5 equiv) /
H2O2 (3 equiv)-NaOH
Ph
O
H
H
N
N
H
O
O
O
N
DCM, 0 oC to RT,
2 h, 99%
THF, 0 oC to RT, 3 h
46%
HO
TBSO
TBSO
O
O
14
5a
15
HO
MsCl (1.1 equiv),TEA (1.5 equiv)
DCM. 0 oC to RT, 3 h, 63%,
or
10 wt% Pd(OH)2
H2 (g) 1 atm,
H
N
H
N
O
TBSO
TBSO
H
MeOH, 6 h, 88%
CBr4 (4 equiv), PPh3 (4 equiv)
TEA (6 equiv),
O
O
O
16
17
DCM, RT, 3 h, 79%
TFA/DCM = 1/1
40 oC, 4 h
N
HO
saturated NaHCO3
47%
H
HO
OH
4
(-)-8-epi-swainsonine
Scheme 4. Synthesis of (À)-8-epi-swainsonine.

556
B. K. Lee et al. / Tetrahedron Letters 54 (2013) 553–556
borane–dimethyl sulfide complex (0 °C to room temperature), fol-
lowed by oxidation with H2O2 to yield the desired primary alcohol
containing pyrrolidine 15 in 46% yield.
References and notes
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a hydrogen atmosphere at room temperature affords the aminoal-
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In summary, the enantioselective synthesis of (À)-8-epi-swains-
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plished in 13 steps. The synthesis of (À)-8-epi-swainsonine
starting from a chiral aziridine has not been reported to the best
of our knowledge. Several interesting features of the approach
include the first application of Sharpless dihydroxylation with
AD-mix-b to a (Z)-3-(aziridin-2-yl)acrylate and the use of a novel,
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This research was supported by the Korea Institute of Science
and Technology and a Grant (No. 2011-0028676) from the crea-
tive/challenging research program of the National Research Foun-
dation of Korea funded by the Ministry of Education, Science and
Technology, and a Grant (No.: A111345) of the Korea Health tech-
nology R&D Project, Ministry of Health & Welfare, Republic of Korea.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.087.