A short and efficient synthesis of (+)-calystegine B2

Article abstract of DOI:10.1016/S0040-4039(00)02262-0

A short synthesis of (+)-calystegine B₂ from (D)-glucose has been achieved, which involves as the key step a triple domino zinc-mediated reductive ring-opening, imine formation and allylation reaction of 6-iodoglucopyranose.

Full text of DOI:10.1016/S0040-4039(00)02262-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1275–1277
A short and efficient synthesis of (+)-calystegine B2
Franc¸ois-Didier Boyera and Issam Hannab,*
aUnite´ de Phytopharmacie et Me´diateurs Chimiques, INRA, Route de Saint-Cyr, F-78026 Versailles, France
bLaboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France
Received 4 December 2000; accepted 9 December 2000
Abstract—A short synthesis of (+)-calystegine B2 from (D)-glucose has been achieved, which involves as the key step a triple
domino zinc-mediated reductive ring-opening, imine formation and allylation reaction of 6-iodoglucopyranose. © 2001 Elsevier
Science Ltd. All rights reserved.
Calystegines1 are polyhydroxylated nortropane alka-
loids, first isolated from the roots of Calystegia sepium
as plant metabolic mediators in the rhizosphere. Re-
cently, they have been found in tuber tissues and in
other plant organs of a large variety of potatoes
(Solanum tuberosum…). This group of alkaloids is of
interest in that most of its members are potent in-
hibitors of glycosidase enzymes.2 Among them (+)-ca-
cycloheptanone intermediate (e.g. 2), which is allowed
to ring-close in the last stage of the synthesis into the
bicyclic aminoketal structure, e.g. calystegine B2
(Scheme 1).
1
Previous reports from our laboratory described the
synthesis of both (+) and (−)-calystegines B2 through
ring enlargement of the protected pseudosymmetric
polyhydroxycyclohexanone derived from
D
-glucose.4a,b
lystegine B2
1 selectively inhibits the rat liver
An alternative route to the aminocycloheptanone inter-
mediate was also investigated via a Diels–Alder reac-
tion between chiral acylnitroso derivatives and a
protected polyhydroxycycloheptadiene.4c In yet another
approach, both enantiomers of calystegine B2 were
synthesized by Depezay et al. using the intramolecular
b-glucosidase activity and the human lysosomal a-
galactosidase A (a-Gal A) with an IC50 value of 30 mM.
Several enantioselective and racemic syntheses of
calystegines have been reported.3–5 All of these pro-
ceeded via an appropriately substituted 5-amino-
cycloaddition of an olefinic oxime derived from
D-glu-
cose.5 Despite their success, these syntheses suffer from
certain drawbacks, in particular their length since more
than ten steps are required to reach the amino cyclo-
heptane system.
H
N
O
HO
HO
HO
NH2
HO
(+)-Calystegine B 2
Scheme 1.
HO
OH
OH
1
In a recent report, we described the facile preparation
of highly functionalized cycloheptenes from galactose
derivatives. In particular, 6-iodogalactopyranose 3 un-
derwent a zinc-mediated triple domino reaction fol-
2
I
Zn,
O
O
OMe
Grubbs catalyst
O
THF,
O
)))
( 5%), rt
Bn
Bn
OTBS
N
O
BnNH2 ,
then
N
O
93-98%
R
O
OTBS
Br
65%
R
OTBS
6:1
3
4
Scheme 2.
* Corresponding author. Fax: +33 1 69 33 30 10; e-mail: hanna@poly.polytechnique.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02262-0

1276
F.-D. Boyer, I. Hanna / Tetrahedron Letters 42 (2001) 1275–1277
I
OMe
OBn
O
Grubbs' catalyst
(7.7%)
)))
,
Zn,
THF
BnO
BnO
BnO
BnO
Bn
Bn
N
N
BnNH2 ,
Br
BnO
CH2Cl2, rt, 97%
Cbz
R
then
73%
OBn
OBn
85:15
OBn
8
CbzCl
NaHCO3
AcOEt
6 R=H
7 R=Cbz
94%
5
1) BH3- DMS,
Et2O,
HO
OH
-30 to 0˚C
BnO
BnO
BnO
Bn
N
Cbz
Bn
2) 30% H2O2,
2N NaOH
+
N
BnO
Cbz
OBn
OBn
84%
10 (23.5%)
9 (60.5%)
H
O
N
1) H2, Pd/C,
AcOH/H2O
HO
PCC, CH2Cl2
93%
BnO
BnO
Bn
9
HO
HO
N
2) NH4OH
79%
Cbz
OH
OBn
1
11
Scheme 3.
lowed by ring-closing olefin metathesis (RCM) to fur-
nish the aminocycloheptene 4 in good yield (Scheme
2).6 Herein we use this method7 as the key-step in a
concise synthesis of (+)-calystegine B2.
cation of the crude product using Dowex® 50W-X8
ion-exchange resin column (0.01 M HCl then 0.5%
NH4OH and 1% NH4OH), followed by silica gel flash
column chromatography (MeOH–H2O 95:5) afforded 1
1
in 79% yield. The H, 13C NMR spectra and specific
The synthesis started from 6-iodoglucopyranose 5,8
rotations ([h]D=+24 (c 1.14, H2O) obtained from the
aqueous solution of 1 are similar to those reported for
(+)-calystegine B2.4b
readily prepared from the cheap and commercially
available methyl-a- -glucopyranoside. As for 3, when 5
D
was subjected to zinc dust in the presence of benzyl-
amine followed by the addition of allyl bromide in
anhydrous THF under sonication, amino diene 69 was
obtained as an 85:15 mixture of diastereomers sepa-
rated by flash column chromatography in 73% com-
bined yield. (Scheme 3).
In conclusion, we have described a rapid (six steps from
5, 25% yield overall) and efficient route to (+)-calyste-
gine B2, involving as the key-step a triple domino
reaction: zinc-mediated reductive ring-opening, imine
formation followed by allylation of 6-iodoglucopyra-
nose derivative. This approach could be used for the
synthesis of other calystegines.
The anti configuration of the new asymmetric center in
the major isomer was assigned later on the basis of the
RCM reaction product, and confirmed in the final stage
of the synthesis. The amino group was then protected
as the benzyl carbamate 7, and the major isomer was
submitted to the ring-closing metathesis reaction10
using Grubbs catalyst (0.077 equiv.) in CH2Cl2 at room
temperature for 4.5 h to afford 8 as a mixture of
atropoisomers in 97% yield. Hydroboration of olefin 8
with borane–methyl sulfide complex (BH3–DMS) in
diethyl ether at 0°C for 18 h followed by oxidative
treatment (30% H2O2 and 2N NaOH for 3 h) gave a
mixture of regioisomeric alcohols 9 and 10 (2.6:1)
which were separated by flash chromatography in 84%
combined yield. Oxidation of the major regioisomer 9
with pyridinium chlorochromate (PCC) in dichloro-
methane provided the desired ketone 11 in 93% yield.
Finally, full deprotection of the triol and the amine
functionality was accomplished by hydrogenolysis with
10% Pd/C in aqueous acetic acid for four days. Purifi-
References
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J=9 Hz, 1 H), 5.66 (m, 1 H), 5.34–4.56 (m, 9 H), 4.14 (d,
J=12 Hz, 1 H), 4.02 (dd, J=7.5 Hz, J=3 Hz, 1 H), 3.90
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(CH), 80.8 (CH), 79.7 (CH), 75.4 (CH2), 74.8 (CH2), 70.2
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1
9. All new compounds were full characterized by H NMR,
13C NMR, IR spectroscopy, mass spectrometry and opti-
cal rotation. Data for 6 (major isomer): [h]D=−19.5 (c
2.84, CHCl3). 1H NMR (300 MHz, CDCl3) l (ppm)=
7.35–7.30 (m, 20 H), 6.00 (ddd, J=18 Hz, J=10.5 Hz,
.
.