A concise approach to (+)-1-epi-castanospermine

Article abstract of DOI:10.1016/j.tetlet.2007.11.033

A concise enantioselective synthesis of (+)-1-epi-castanospermine (2) is described, which featured the use of chiral non-racemic tetramic acid derivative 5 as a synthetic equivalent of the challenging synthon A through a highly diastereoselective vinylogo

Full text of DOI:10.1016/j.tetlet.2007.11.033

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Tetrahedron Letters 49 (2008) 383–386
A concise approach to (+)-1-epi-castanospermine
Tian-Jun Wu and Pei-Qiang Huang*
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, PR China
Received 30 August 2007; revised 3 November 2007; accepted 6 November 2007
Abstract—A concise enantioselective synthesis of (+)-1-epi-castanospermine (2) is described, which featured the use of chiral
non-racemic tetramic acid derivative 5 as a synthetic equivalent of the challenging synthon A through a highly diastereoselective
vinylogous Mukaiyama type reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
Sugar mimetics, such as polyhydroxylated pyrrolidine,
piperidine, pyrrolizidine, and indolizidine alkaloids,
known as azasugars, show important bioactivities.1
Among them, castanospermine (1), an alkaloid first iso-
lated2 from the seeds of Castanospermum australe and
then from the dried pod of Alexa leiopetala, has
attracted considerable attention. Because of its powerful
inhibitory activities toward a- and b-glucosidases,3 cast-
anospermine (1) shows considerable potential as an anti-
viral agent in the treatment of HIV,4 hepatitis C,5 and
HSV-16 infections. Castanospermine and its stereomers
also have potential use in the inhibition of progression
of multiple sclerosis,7 angiogenesis, cancer,8 and diabe-
Scheme 1. Retrosynthetic analysis of polyhydroxylated alkaloids
(azasugars).
tes.9 Several stereomers of castanospermine have also
been isolated from natural sources.10 The synthetic 1-
epi-castanospermine (2)11 was suggested to possess
approach to the azasugars such as castanospermine (1)
and hyacinthacine B4 (3).15
anti-HIV activity, and thus constitutes a valuable syn-
thetic target for biological activities evaluation.
Although a number of umpoled methods have been
developed,16 and the generation of chiral non-racemic
In addition, these alkaloids also provide a natural
platform for exploring new synthetic methodologies.
N-a-carbanion of 4-hydroxy-2-pyrrolidinone A has been
reported,13,17 the C–C bond formation based on
So far numerous strategies have been developed for
the enantioselective synthesis of castanospermine and
synthon A remains a challenging problem in carbanion
chemistry due to quick proton exchange17 or b-elimina-
other polyhydroxylated alkaloids as well as their stereo-
mers.11,12 However, novel, efficient, and flexible methods
are still highly demanding. That the carbanionic synthon
A-based strategy as illustrated retrosynthetically in
Scheme 113,14 is conceptually attractive for a general
tion if the hydroxyl group is protected.13,18 Recently, we
reported a flexible approach to 5-alkyl tetramic acid
derivatives based on the C-5 alkylation of tetramic acid
derivative 5, which was used as a synthetic equivalent of
4-hydroxy-2-pyrrolidinone
5-carbanionic
synthon
A.19,20 With the aim to develop a general asymmetric
approach to polyhydroxylated alkaloids, we now
describe the extension of this method from alkylation
to a-hydroxyalkylation and the asymmetric synthesis
of 1-epi-castanospermine (2).
Keywords: Castanospermine; Tetramic acid; Synthon; Mukaiyama
type reaction.
*
Corresponding author. Tel.: +86 592 2180992; fax: +86 592
2186400; e-mail: pqhuang@xmu.edu.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.033

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T.-J. Wu, P.-Q. Huang / Tetrahedron Letters 49 (2008) 383–386
and reappeared when the temperature returned to
20 °C. These NMR experiments show that the aldol
products observed in the NMR spectra are rotamers
instead of diastereomers, as observed previously.19 This
was confirmed at a later stage (8!10). The stereo-
chemical assignment was also carried out at a later stage
(vide infra), which revealed that the newly formed
stereocenters are erythro (anti), and the relationship with
the adjacent stereocenter is threo (syn).
Thus the vinylogous Mukaiyama type reaction between
6 and 7 established the correct configurations required
for the synthesis of castanospermine and its C-1 epimer.
This stereoselection can be rationalized by transition
state21,22 T1, which is favored over T2 (Fig. 1). The reac-
tion of 6 with aldehyde 7 is distinct from those reported
by Casiraghi not only in the stereoselection, but also in
the reaction conditions used for their formations (in
THF at ꢀ78 °C versus in diethyl ether at ꢀ85 °C).
Scheme 2.
Our initial efforts have been devoted to explore the use
of the vinylogous enolate derived from tetramic acid
derivative 5. Unfortunately, although the alkylation of
this enolate shows excellent diastereoselectivities,19 its
reaction with iso-butanal gave four diastereomers with
a modest ratio of 2:4:27:67.
Now the stage was set for the synthesis of 1-epi-castano-
spermine (2) (Scheme 3). To this end, compound 8 was
treated with a 10% HCl solution in THF at 30 °C to give
the desired tetramic acid 9, and then compound 9 was
25
treated with NaBH4 in the presence of HOAc at ꢀ10
to ꢀ5 °C for 9 h to give 10 as the sole diastereomer
In the light of the high diastereoselectivities observed in
the vinylogous aldol reaction of heterocyclic silyloxy
dienes,21,22 extensively studied by Casiraghi and
co-workers, we turned our attention to explore the use
of the vinylogous silyl enol ether23 6, easily derived from
the tetramic acid derivative 5 (Scheme 2). Accordingly,
compound 5 was treated with LDA in THF at ꢀ78 °C
for 1 h. The resulted vinylogous enolate was quenched
with trimethylsilyl chloride and allowed to warm up to
ꢀ10 °C, and then stirred for 2 h. The in situ generated
vinylogous silyl enol ether 6 was reacted, in the presence
of tin tetrachloride at ꢀ78 °C, with 4-O-(4-methoxy-
benzyl)-2,3-bis-(O-benzyl)-L-threose (7)24 for 3.5 h. To
our delight, the desired hydroxyalkylated product 8
was obtained as the sole product in 60% yield. Both
judged by the NMR analysis. The two hydroxyl groups
1
the H and 13C NMR spectra of the product are quite
complex, a 2.2:1 ratio of mixture was observed. The fact
that the HPLC analysis showed only one product in 99%
de allowed us to assume that the complex peaks which
1
appeared in both the H and 13C NMR spectra of 8
are rotameric in nature, which is due to the slow rota-
tion around the C–N bond.18 To confirm this assump-
tion, both the 1H and 13C NMR spectra of 8 were
recorded in DMSO-d6 at 20 °C and 95 °C, respectively.
The peaks of the minor isomer disappeared at 95 °C
Figure 1.
Scheme 3.

T.-J. Wu, P.-Q. Huang / Tetrahedron Letters 49 (2008) 383–386
385
were protected (NaH, BnBr, n-Bu4NI) to afford the
desired di-benzylated product 11 in 72% yield. Treat-
ment of compound 11 with I2 in refluxing methanol26
resulted in the selective cleavage of the O-PMB group,
which furnished alcohol 12 in 76% yield.
Tosylation of alcohol 12 (p-TsCl/pyr.) led to tosylate 13
in 96% yield. Cleavage of the N-PMB group under
Yoshimura’s conditions27 (CAN, MeCN/H2O = 9:1)
for 5 h at rt gave the desired lactam 14 in 85% yield.
The key cyclization of 14 was undertaken by treating
with n-BuLi in THF at ꢀ78 °C for 0.5 h, then allowed
to warm up and stir overnight. The desired indolizidi-
none 15 was obtained in 84% yield. The relative stereo-
Scheme 4.
1
chemistry of 15 was determined, first by H–1H COSY
1
and H–13C HMQC experiments to make the proton
achiral aldehydes is in progress in these laboratories
and will be reported in due course.
assignments, and then by NOESY experiment. These
experiments not only allowed determining the erythro
(anti)/threo (syn) relationship of the stereocenters
formed by the vinylogous Mukaiyama type reaction
(6!8), but also determined the stereochemistry of the
reduction (9!10), which indicated a 1,3-syn relationship
between the C-3 and C-5.
Acknowledgments
The authors are grateful to the NSFC (20390050,
20572088, 20602028), Qiu Shi Science & Technologies
Foundation, and the program for Innovative Research
Team in Science & Technology (University) in Fujian
Province for financial support. We thank Professor Y.
F. Zhao for the use of her Bruker Dalton Esquire
3000 plus LC–MS apparatus.
The stereochemistry of the reduction (NaBH4 in HOAc/
CH2Cl2) can be understood by Evan’s directed reduc-
tion model25 (Fig. 2). In this singular situation merging
an alicyclic-cyclic b-hydroxy ketone system, the forma-
tion of the 1,3-syn-diol can be explained by the Evans’
model (intramolecular hydride delivery).
References and notes
The subsequent reduction of 15 with borane dimethyl
sulfide complex (BH3ÆSMe2) proceeded smoothly to give
indolizidine 16 in 92% yield (Scheme 4). Finally, cleav-
age of the four benzyl groups in 16 was achieved by
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epi-castanospermine (2) {½aꢁD +3.8 (c 0.54, MeOH);
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