Asymmetric synthesis of fagomine and its congeners

Article abstract of DOI:10.1016/S0957-4166(01)00136-7

The total synthesis of fagomine and its congeners 1-3 has been achieved starting from D-serine-derived Garner aldehyde 5 by catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring followed by dihydroxylation.

Full text of DOI:10.1016/S0957-4166(01)00136-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 817–819
Asymmetric synthesis of fagomine and its congeners
Yasunori Banba,a Chiemi Abe,a Hideo Nemoto,a Atsushi Kato,b Isao Adachib and
Hiroki Takahataa,*
aFaculty of Pharmaceutical Sciences, Toyama Medical & Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan
bDepartment of Hospital Pharmacy, Toyama Medical & Pharmaceutical University, Sugitani 2630, Toyama 930-0194, Japan
Received 28 February 2001; accepted 14 March 2001
Abstract—The total synthesis of fagomine and its congeners 1–3 has been achieved starting from
D-serine-derived Garner
aldehyde 5 by catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring followed by dihydroxylation.
© 2001 Elsevier Science Ltd. All rights reserved.
Azasugar inhibitors of glycosidases and related enzymes
are the subject of intense current interest.1–3 Polyhyd-
roxylated piperidines and their synthetic analogues
have attracted a great deal of attention in recent years
due to their ability to mimic sugars, and competitively
and selectively inhibit glycosidases and glycosyltrans-
ferases,4 the carbohydrate processing enzymes. These
attributes make hydroxylated piperidines (azasugars)
likely therapeutic agents for the treatment of diseases
related to metabolic disorders involving carbohydrates
such as diabetes, cancer, AIDS, and viral infections,5
where glycoprotein processing is crucial. Recently three
fagomine isomers 1–3 were found from Xanthocercis
zambesiaca occurring in southern Africa in dry forest.6
Among them, fagomine 1 and 3-epi-fagomine 2 have
been shown to have activity against mammalian a-glu-
cosidase and b-galactosidase.6 More recently 1 was
found to have a potent antihyperglycaemic effect in
streptozocin-induced diabetic mice and a potentiation
of glucose-induced insulin secretion.7 To date the asym-
metric synthesis of 1 has been reported twice,8 but
asymmetric synthesis of 2 and 3,4-di-epi-fagomine 3 is
not known. In a project devoted to the chiral synthesis
of glycosidase inhibitors, we envisaged the preparation
of a new common chiral building block, hydroxy-
methylpiperidene 4, which seems to be an ideal precur-
sor for the synthesis of dihydroxypiperidinols. Herein,
we describe a new entry to the synthesis of fagomine
and its congeners by the preparation of 4 in a straight-
forward and stereoselective manner using Garner alde-
hyde 5 and catalytic ring-closing metathesis (RCM) for
the construction of the piperidine ring.9
Our synthesis of 4 began with the Wittig reaction of the
D
-serine-derived Garner aldehyde 5.10 The treatment of
5 with methyltriphenylphosphonium iodide in the pres-
ence of sodium bis(trimethylsilyl)amide gave the olefin
6 in 63% yield11 (Scheme 1). Hydrolysis of 6 with
p-toluenesulfonic acid in MeOH followed by O-silyla-
tion then afforded 7 in 72% yield. N-Alkylation of 7
with 4-bromo-1-butene under several conditions
resulted only in recovery of the starting material 7.12
However, use of a three-step sequence (1. deprotection
of N-Boc group; 2. alkylation; 3. N-protection)
afforded the butenylated product 8 in 60% yield. RCM
of 8 with Grubbs’ catalyst, bis(tricyclohexylphos-
phine)benzylidineruthenium(IV) dichloride under stan-
dard conditions afforded the desired intermediate 4
{[h]2D7 −150.1 (c 1.04, CHCl3)} in 97% yield.
* Corresponding author. E-mail: takahata@ms.toyama-mpu.ac.jp
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00136-7

818
Y. Banba et al. / Tetrahedron: Asymmetry 12 (2001) 817–819
Scheme 1. Reagents and conditions: (a) Ph3P+CH3I−, NaN(THF)2, THF; (b) (i) p-TsOH–H2O, MeOH, (ii) TBDPSCl, DMAP,
imidazole, CH2Cl2; (c) (i) CF3COOH, CH2Cl2, (ii) 4-bromo-1-butene, K2CO3, CH3CN, (iii) (Boc)2O, Et3N, CH2Cl2; (d) Grubbs’
catalyst, CH2Cl2.
With 4 in hand, the stereoselective dihydroxylation of
the double bond could be examined. Under modified
Upjohn conditions,14 treatment of 4 with a catalytic
amount of K2OsO4·2H2O (5 mol%) and 4-methylmor-
pholine N-oxide (1.5 equiv.) as co-oxidant gave diol 9
as a single diastereoisomer in high 92% yield15 (Scheme
2). Deprotection of 9 with 10% hydrochloric acid in
dioxane followed by treatment with ion-exchange resin
(Dowex® 1X2 OH− form) afforded 3-epi-fagomine 216
in 91% yield. It was found that dihydroxylation
occurred exclusively at the less hindered anti-side to the
siloxymethyl substituent.
In order to obtain both 1 and 3 containing trans-diols
at the 3 and 4 positions, we introduced an epoxy
functionality into the double bond. The dioxirane gen-
erated in situ from oxone® with 1,1,1-trifluoroacetone
according to a recent procedure17 reacted with 4 to give
a mixture of stereoisomeric epoxy compounds 1013 and
1113 which were separated by medium pressure chro-
matography in high 91% yield though the diastereo-
selectivity was low (ds: 33%)18 (Scheme 3). The
stereochemistry of the epoxide products was determined
by stereoselective cleavage of the epoxy ring using
Super-Hydride®. Treatment of 10 and 11 with Super-
Hydride® in THF led to the hydroxy compounds 12
(96%) and 13 (86%), respectively. The complete depro-
tection of 12 and 13 with hydrochloric acid in methanol
followed by treatment with ion-exchange resin of the
resulting salts afforded the known (2R,3S)- and
(2R,3R)-3-hydroxy-2-hydroxymethylpiperidines 1413,19
and 15,13,20 respectively, in quantitative yields. Acidic
hydrolysis of the epoxy group of 10 was examined with
a mixture of H2SO4/dioxane/H2O in a ratio of 0.2/3/2
mL21 followed by treatment of the ion-exchange resin
to exclusively give fagomine 116 in 75% yield. This high
selectivity may be rationalized as follows: attack of
H2O with back-side displacement of the leaving oxygen
in the epoxy-substituted ring occurs at the more remote
4 position because nucleophilic attack at the 3 position
is syn-oriented with respect to the adjacent hydroxy-
methyl substituent at the 2 position. Similar treatment
of 11 afforded a mixture of 1 and 316 in 78% yield and
a product ratio of 1.3:1, which were separated by
chromatography. In this case, due to the anti-relation-
ship between the hydroxymethyl substituent at the 2
position and attack orientation, there is less steric dif-
ference between the two possible sites of ring opening
and back-side attack of H2O to the epoxy ring can
occur at both the 3 and 4 positions.
In conclusion, we have described a rapid and straight-
forward asymmetric synthesis of fagomine and its con-
geners 1–3 (the first total synthesis for 2 and 3) using a
common chiral piperidine 4. The products 1–3 and
intermediate 4 are expected to be of great utility as
chiral building blocks in the synthesis of piperidine-
derived alkaloids.22
Scheme 2. Reagents and conditions: (a) cat. K2OsO4·2H2O,
4-methylmorpholine N-oxide, acetone, H2O; (b) (i) 10% HCl,
dioxane, (ii) Dowex 1X2 (OH−) form.
Scheme 3. Reagents and conditions: (a) Oxone®, CF3COCH3, NaHCO3, aq. Na2·EDTA, CH3CN; (b) Super-Hydride®, THF; (c)
(i) 10% HCl, dioxane, (ii) Dowex 1X2 (OH− form); (d) H2SO4, dioxane, H2O.

Y. Banba et al. / Tetrahedron: Asymmetry 12 (2001) 817–819
819
References
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