A straightforward route to indolizidine and quinolizidine analogs as new potential antidiabetics

Article abstract of DOI:10.1055/s-2003-37112

New polyhydroxylated indolizidine and quinolizidine analogs of castanospermine are efficiently obtained by a double reductive amination of enantiopum cyclic ketoaldehydes. As rigidified mimics of disaccharides, these compounds are expected to exhibit sign

Full text of DOI:10.1055/s-2003-37112

LETTER
333
A Straightforward Route to Indolizidine and Quinolizidine Analogs as new
Potential Antidiabetics
A
S
traightforwar
hrdolizidii
s
uinolizid
t
ine
A
n
i
alogs ne Gravier-Pelletier, William Maton, Yves Le Merrer*
Université René Descartes, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, 45 rue des Saints-
Pères, 75270 Paris Cedex 06, France
Fax +33(1)42868387; E-mail: Yves.Le-Merrer@biomedicale.univ-paris5.fr
Received 24 September 2003
If considerable synthetic efforts have been devoted to the
Abstract: New polyhydroxylated indolizidine and quinolizidine
synthesis of iminosugar analogs5 and have sometimes
analogs of castanospermine are efficiently obtained by a double
reductive amination of enantiopure cyclic ketoaldehydes. As rigidi-
shown interesting inhibitory activity,6 to our knowledge,
no indolizidine or quinolizidine analogs such as 1 and 2
(Figure 2) have ever been evaluated as potential glyco-
sidase inhibitors. Furthermore, compounds 1 and 2 (poly-
hydroxy-octahydroindole and -decahydroquinoline,
respectively) display a structure related to that encoun-
tered in castanospermine5 which is a powerful inhibitor of
α-glucosidase. So, taking advantage of the strategy that
we recently described7 towards the efficient carbocyclisa-
tion of D-manno or L-ido bis-epoxide readily obtained
from D-mannitol, our retrosynthetic analysis is outlined in
Figure 2.
fied mimics of disaccharides, these compounds are expected to
exhibit significant antidiabetic properties.
Key words: glycosidases, alkaloids, carbocycles, bicyclic com-
pounds, reductive amination
Our field of investigations concerns α-glucosidase inhib-
itors. The activity of acarbose,1 voglibose2 or miglitol3 has
already been demonstrated as inhibitors of intestinal di-
gestive enzymes (Figure 1) and these compounds were
approved to treat non-insulinodependant mellitus diabetes
in humans.4 Both the naturally occurring voglibose and
acarbose are believed, in the same way as other carbohy-
drate mimics such as polyhydroxylated piperidines (like
miglitol), pyrrolidines, indolizidines and pyrrolizidines,
to mimic the charge of the presumed transition state for
enzymatic glycoside hydrolysis, due to the protonation of
their nitrogen atom in the enzyme active site.
OH
OP
OP
HO
OH
SiO
OP
SiO
OP
*
*
*
*
*
*
*
*
*
*
*
S
*
*
n
n
S
N
O
HO
R
O
1 : n = 1, 2 : n = 2
n = 1, 2
OH
HO
HO
OH
NH
Si
PO
OP
OH
S
S
*
*
+
HO
HO
OH
HN
*
*
O
O
HO
CH3
O
Si = TBDMS
Figure 2 Retrosynthetic analysis.
HO
OH
OH
O
Voglibose
HO
O
OH
OH
OH
The key steps involve a one-pot tandem alkylation-cy-
clization of C2-symmetrical L-ido-bis-epoxide leading to a
polyhydroxy cyclohexanone masked as its dithioketal,
followed by formal homologation with one or two carbon
atom moieties to give the corresponding aldehyde. After
dithioketal hydrolysis, a double reductive amination of the
resulting 1,4- or 1,5-dicarbonyl compound achieves the
construction of the structural skeleton. To reach an abso-
lute configuration at chiral carbon atoms of the targeted
compounds as close as possible to that of castanosper-
mine, the 1,2:5,6-dianhydro-3,4-O-methylethylidene-L-
iditol 3 (Scheme 1) has been chosen as starting material.
HO
O
OH
HO
HO
HO
OH
O
OH
N
OH
OH
HO
H
OH
OH
Acarbose
Miglitol
HO
N
Castanospermine
Figure 1 Inhibitors of α-glucosidases.
We previously showed that carbocyclization could be di-
rected to the major formation of either dithioketal of poly-
hydroxy-cycloheptanone or -cyclohexanone depending
on the nature of the protective group for the central diol of
Synlett 2003, No. 3, Print: 19 02 2003.
Art Id.1437-2096,E;2002,0,02,0333,0336,ftx,en;G28302ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

334
C. Gravier-Pelletier et al.
LETTER
O
O
O
O
O
O
OSi
OSi
OSi
Path a
O
d
e
b
A
OHC
OHC
S
S
S
S
O
5 : A = OTs
6 : A = CN
7
8
O
O
c
O
OSi
a
Si = TBDMS
OSi
HO
O
O
S
S
3
O
O
O
4
O
O
O
OSi
OSi
D-gluco
e
f
h
2
OHC
2
OHC
A
S
S
S
S
O
Path b
9 : A =
10 : A = CH2CO2Et
11
12
CH CO2Et
g
Scheme 1 Reagents and conditions: (a) 2-tert-Butyldimethylsilyl-1,3-dithiane, THF–HMPA, 9:1, tert-BuLi, –78 °C to –30 °C, then 3, 15
min, 72%; (b) TsCl, DMAP, Et3N, CH2Cl2, 98%; (c) NaCN, DMSO, 90 °C, 92%; (d) DIBAL-H, toluene, –78 °C, 78%; e) NBS, (CH3)2CO,
H2O, –50 °C, 75%; (f) i. DMSO, SO3, pyridine, Et3N, CH2Cl2; ii. (EtO)2POCH2CO2Et, t-BuOK, –78 °C, THF, 71% from 4; (g) TsNHNH2,
NaOAc, THF:H2O, 80 °C, 93%; (h) DIBAL-H, hexane, –78 °C, 60%.
the bis-epoxide.7 Thus, condensation of the tert-butyllith- PhCH3, 0 °C}14 or magnesium turnings (MeOH, reflux)15
ium generated lithio derivative of 2-tert-butyldimethyl- were ineffective and sodium borohydride in the presence
silyl-1,3-dithiane on the L-ido-bis-epoxide 3, in of lithium iodide (MeOH, reflux)16 only afforded the me-
THF:HMPA 9:1 at –30 °C (Scheme 1) led to the expected thyl ester resulting from transesterification. To overcome
major formation of the D-gluco-cyclohexanone derivative this difficulty, we finally demonstrated that tosyl-
4 (72% yield).8
hydrazide in THF at 80 °C followed by slow addition of
sodium acetate in H2O17 cleanly furnished the saturated
ester 10 (93%). Then, reduction with DIBAL-H afforded
the aldehyde 11 (60%) and the ketoaldehyde 12 was ob-
tained under the same conditions as previously (75%).
According to the preparation of either indolizidine 1 or
quinolizidine 2 analogs (path a or b), the primary alcohol
function of the common intermediate 4 was transformed
by elongation with one or two carbon atoms into the ke-
toaldehyde 8 or 12, respectively. The preparation of alde- We next turned to the further transformation of ketoalde-
hyde 7 (path a) involved activation of the hydroxy group hydes 8 and 12 (Scheme 2), which involved a double re-
of 4 as tosylate 5 (98%), followed by substitution with so- ductive amination at the origin of indolizidine or
dium cyanide to afford nitrile 6. Subsequent reduction by quinolizidine analogs, respectively. For example, treat-
DIBAL-H at –78 °C led to the expected aldehyde 7 ment of 8 in methanol at 0 °C with sodium cyanoborohy-
(78%). Finally, hydrolysis of the dithioketal moiety by N- dride and benzylamine–acetic acid (1 equiv) in
bromosuccinimide in acetone–H2O9 at –50 °C gave the methanol18 afforded the expected indolizidine analog 13
ketoaldehyde 8 (75%). On the other hand, ketoaldehyde (50%).19 1H and 13C NMR analysis established without
12 (path b) was obtained by oxidation of the alcohol func- ambiguity firstly, the absence of epimerization during the
tion of 4 by SO3–pyridine followed by a Wittig type reac- reaction and secondly, the formation of a single stereo-
tion with the anion of triethylphosphonoacetate generated isomer displaying a cis relationship at the ring junction
by potassium tert-butoxide to afford the corresponding (J7a,3a = ca. 4.4 Hz). Finally, hydrogenolysis of the N-
α,β-ethylenic ester 9 (71% overall yield). Due to the pres- benzyl bond in the presence of palladium hydroxide fol-
ence of sulphur atoms in compound 9 the selective reduc- lowed by acidic hydrolysis of both acetonide and silyl
tion of its double bond was troublesome and required ether in trifluoroacetic acid–H2O (9:1) and subsequent
careful choice of experimental conditions. Thus, neither purification by ion exchange chromatography led to the
the hydrogenation done in the presence of Wilkinson’s desired indolizidine analog 19 (43%). Taking advantage
catalyst (20 °C, toluene10 or P = 6 bar, 60 °C11 or benz- of the late introduction of the primary amine, in order
ene–EtOH, P = 6 bar, 60 °C12), nor heterogeneous hydro- to target bicyclic analogs of voglibose and miglitol, we
genation (Pd black, EtOH, 20 °C) or rhodium on alumina performed the same sequence of reactions with the O-
(EtOAc, 20 °C)13 gave any expected product. Both reduc- persilylated serinol derivative and with ethanolamine, as
tion involving copper(I) hydride cluster {[(Ph3P)CuH]6, aglycon part. Thus, the respective N-substituted bicyclic
Synlett 2003, No. 3, 333–336 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Straightforward Route to Indolizidine and Quinolizidine Analogs
335
O
N
OH
O
H
OSi
HO
H
OH
b
19 : R = H
(43%)
b
c
a
(HOCH2)2CH
(80%)
(98%)
21 : R =
n = 1
c
or c
23 : R = HO(CH2)2
H
H
N
R
R
13 : R = Bn
(SiOCH ) CH
(50%)
(75%)
(66%)
15 : R =
2 2
O
17 : R = HO(CH2)2
O
OSi
O
O
OH
OHC
n
OSi
HO
H
OH
b
(86%)
20a : R = H
O
H
b
c
(70%)
(69%)
22a : R = (HOCH2)2CH
8 : n = 1
12 : n = 2
c
or c
24a : R = HO(CH2)2
H
R
H
N
N
R
a
a
+
n = 2
OH
O
O
HO
H
OH
OSi
b
20b : R = H
(75%)
b
H
c
(85%)
(80%)
22b : R = (HOCH2)2CH
24b : R = HO(CH2)2
or c
c
H
H
R
N
N
R
b
14 : R = Bn
(SiOCH ) CH
(50%)
(55%)
(70%)
a/b = 25/75
a/b = 60/40
a/b = 40/60
16 : R =
18 : R = HO(CH2)2
2 2
Scheme 2 Reagents and conditions: (a) NaBH3CN (2 equiv), MeOH, 0 °C then RNH2⋅HOAc (1 equiv), MeOH, 0 °C to 20 °C; (b) i. H2,
Pd(OH)2, EtOH, 20 °C; ii. TFA–H2O, 9:1; (c) TFA–H2O, 9:1.
compounds 21 and 23 have been obtained by double re- stituted to serve as a reference concerning the eventual
ductive amination (75% and 66%, respectively) and acidic biological effect of N-substitution of such derivatives.
hydrolysis (80% and 98%, respectively).
The biological activity of these new compounds was
tested on various glycosidases such as α-D-glucosidase
from Bacillus stearothermophilus, β-D-glucosidase from
almonds, α-D-mannosidase from Jack beans, and α-L-fu-
cosidase from bovine kidney. Among them, only com-
pounds 22a and 22b exhibited significative activity (18
and 70 µM, respectively) on α-L-fucosidase. Further eval-
uations of potential activity of all these compounds to-
wards digestive enzymes are now under progress and will
be reported later on.
In a similar manner, access to the quinolizidine-like ana-
logs 20, 22 and 24 has been carried out from the ketoalde-
hyde 12. It should be noted that, in the latter cases, the
double reductive amination led to a mixture of two
epimers at the bicyclic junction, which were easily sepa-
rated by flash chromatography, and for which the cis/
trans ratio varied from 25/75 to 60/40 in 50 to 70% yield
(J4a,8a = ca. 3.2 and 12.8 Hz for the cis and trans isomer,
respectively). Then complete deprotection of the corres-
ponding polyhydroxy decahydroquinoline was carried out
under similar conditions as above to afford 20ab, 22ab,
24ab in good yields.
Acknowledgment
The authors are grateful to Dr. G. Bertho (LCBPT) for his assistance
in NMR studies.
In summary, various enantiopure indolizidine and quino-
lizidine analogs (19–24) were obtained in a straightfor-
ward manner via a double reductive amination of a
dicarbonyl compound. The latter was resulting from the
formal one- or two-carbon atom elongation of the lateral
primary alcohol function of a polyhydroxycyclohexanone
easily available from D-mannitol via a tandem alkylation–
cyclization reaction. According to the strategy, the ana-
logues of indolizidine and quinolizidine have been either
N-substituted with the aglycon part of voglibose or migli-
tol, two compounds used in diabetes treatment or unsub-
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LETTER
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obtained for all new compounds.
the residue afforded the indolizidine or quinolizidine analog
in yield ranging from 50% to 75% according to the
ketoaldehyde and to the primary amine involved.
Selected physical data for compounds 15, 16a and 16b
([α]D20 in CH2Cl2 1H NMR [250 MHz unless indicated, δ
(ppm), J (Hz) and 13C NMR (62.5 MHz, δ(ppm)] in CDCl3.
Hydrogen and carbon atoms of the heterocycle have been
numbered according to the IUPAC nomenclature rules, and
for the N-side chain by A, B and C:
15: [α]D20 +24.5 (c 1.1). 1H NMR (500 MHz): δ = 3.89 (ddd,
1 H, J6,7′ = 9.5 Hz, J6,5 = 9.2 Hz, J6,7 = 5.0 Hz, H6), 3.75 (dd,
1 H, JA,A′ = 10.4 Hz, JA,B = 6.2 Hz, HA), 3.72 (dd, 1 H,
JA′,A = 10.4 Hz, JA′,B = 5.0 Hz, HA′), 3.60 (dd, 1 H,
JC,C′ = 10.0 Hz, JC,B = 5.9 Hz, HC), 3.57 (dd, 1 H, JC′,C = 10.0
Hz, JC′,B = 6.4 Hz, HC′), 3.44 (dd, 1 H, J4,3a = 10.0 Hz,
J4,5 = 9.2 Hz, H4), 3.36 (ddd, J7a,3a = J7a,7′ = 4.4 Hz, J7a,7 = 2.9
Hz, 1 H, H7a), 3.26 (dd, 1 H, J5,6 = J5,4 = 9.2 Hz, H5), 2.97–
2.87 (m, 2 H, HB,2′), 2.83 (ddd, 1 H, J2,2′ = 14.8 Hz, J2,3′ = 9.4
Hz, J2,3 = 5.6 Hz, H2), 2.15 (ddd, 1 H, J7,7′ = 14.2 Hz,
(9) Gravier-Pelletier, C.; Maton, W.; Lecourt, T.; Le Merrer, Y.
Tetrahedron Lett. 2001, 42, 4475.
(10) Shimizu, S.; Nakamura, S.; Nakada, M.; Shibasaki, M.
Tetrahedron 1996, 42, 13363.
(11) Harmon, R. E.; Parsons, J. L.; Cooke, D. W.; Gupta, S. K.;
Schoolenberg, J. J. Org. Chem. 1969, 11, 3684.
(12) In this case, an unexpected lactone, resulting from double
bond reduction followed by transketalization and subsequent
lactonization, was isolated in a non-reproducible 63% yield
(Figure 3).
J
7,6 = 5.0 Hz, J7,7a = 2.9 Hz, H7), 2.13–2.06 (m, 1 H, H3a),
1.86–1.73 (m, 2 H, H3,3′), 1.42 (ddd, 1 H, J7′,7 = 14.2 Hz,
J7′,6 = 9.5 Hz, J7′,7a = 4.4 Hz, H7′), 1.38, 1.36 (2 s, 6 H,
CMe2), 0.88 (s, 27 H, t-Bu), 0.05 (s, 18 H, SiMe2). 13C NMR:
δ = 109.1 (CMe2), 83.9 (C5), 79.1 (C4), 69.4 (C6), 63.3, 59.3
(CA,C), 60.7, 59.4 (C7a,B), 44.9 (C2), 41.9 (C3a), 35.3 (C7),
29.7 (C3), 27.0 (CMe2), 25.9, 18.3, 18.2 (t-Bu), –4.5, –4.8,
–5.4 (SiMe2). HRMS (CI, CH4) calcd for C32H68NO5Si3 [M+
+ 1]: 630.4405. Found: 630.4393.
16a: [α]D20 +14 (c 1.0). 1H NMR: δ = 4.12 (dd, 1 H,
J5,4a = 11.1 Hz, J5,6 = 9.1 Hz, H5), 3.95 (ddd, 1 H, J7,8 = 11.0
Hz, J7,6 = 9.0 Hz, J7,8′ = 3.8 Hz, H7), 3.72 (dd, 1 H,
JA′,A = 10.3 Hz, JA′,B = 6.9 Hz, HA′), 3.56 (dd, 1 H,
OH
O
O
OTBDMS
JA,A′ = 10.3 Hz, JA,B = 4.6 Hz, HA), 3.60–3.49 (m, 2 H, HC,C′),
S
S
3.24 (dd, 1 H, J6,7 = J6,5 = 9.0 Hz, H6), 3.20–3.10 (m, 1 H,
HB), 3.06 (ddd, 1 H, J8a,4a = J8a,8 = J8a,8′ = ca. 3.2 Hz, H8a),
2.93–2.77 (m, 1 H, H2), 2.39 (ddd, 1 H, J8,8′ = 14.7 Hz,
J8,7 = J8,8a = 3.2 Hz, H8), 2.26 (ddd, 1 H, J2′,2 = J2′,3′ = 11.5
Hz, J2′,3 = 1.9 Hz, H2′), 2.04–1.85 (m, 1 H, H4), 1.81–1.53
(m, 3 H, H4a,3,3′), 1.52–1.40 (m, 1 H, H4′), 1.38 (s, 6 H,
CMe2), 1.40–1.34 (m, 1 H, H8′), 0.88, 0.87 (2 s, 27 H, t-Bu),
0.09, 0.08, 0.06, 0.04, 0.02 (s, 18 H, SiMe2). 13C NMR: δ =
108.7 (CMe2), 85.4 (C6), 74.9 (C5), 68.6 (C7), 62.9 (CA), 59.8
(CB), 59.4 (CC), 58.8 (C8a), 47.8 (C2), 40.0 (C4a), 37.5 (C8),
30.2 (C3), 27.1, 26.9 (CMe2), 25.9, 18.2 (t-Bu), 22.0 (C4),
–4.4, –4.7, –5.4, –5.6 (SiMe2). HRMS (CI, CH4) calcd for
C33H70NO5Si3 [M+ + 1]: 644.4562. Found: 644.4556.
16b: [α]Hg, 36520 +5 (c 1.0). 1H NMR: δ = 3.75 (dd, 1 H,
Figure 3
(13) Suenaga, K.; Araki, K.; Sengoku, T.; Uemura, D. Org. Lett.
2001, 4, 527.
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Lett. 2001, 42, 4091.
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Am. Chem. Soc. 1996, 118, 4711. (b) Hudlicky, T.; Sinai-
Zingde, G.; Natchus, M. G. Tetrahedron Lett. 1987, 28,
5287.
(16) Azami, H.; Barrett, D.; Matsuda, K.; Tsutsumi, H.;
Washizuka, K.; Sakurai, M.; Kuroda, S.; Shirai, F.; Chiba,
T.; Kamimura, T.; Murata, M. Bioorg. Med. Chem. 1999, 7,
1665.
JA′,A = 10.4 Hz, JA′,B = 8.2 Hz, HA′), 3.71 (dd, 1 H,
JA,A′ = 10.4 Hz, JA,B = 4.6 Hz, HA), 3.81–3.66 (m, 1 H, H7),
3.59 (dd, 1 H, JC,C′ = 10.0 Hz, JC,B = 5.3 Hz, HC), 3.53 (dd, 1
H, JC′,C = 10.0 Hz, JC′,B = 7.4 Hz, HC′), 3.32 (dd, 1 H,
(17) Magnus, P.; Gallagher, T.; Brown, P.; Huffman, J. C. J. Am.
Chem. Soc. 1984, 106, 2105.
J6,7 = J6,5 = 9.1 Hz, H6), 3.27–3.14 (m, 1 H, HB), 2.97 (dd, 1
(18) Manescalchi, F.; Nardi, A. R.; Savoia, D. Tetrahedron Lett.
1994, 35, 2775.
H, J5,6 = 10.8 Hz, J5,4a = 9.1 Hz, H5), 2.91–2.80 (m, 1 H, H2),
2.48 (ddd, 1 H, J8a,4a = 12.8 Hz, J8a,8′ = 9.0 Hz, J8a,8 = 4.0 Hz,
H8a), 2.45–2.31 (m, 2 H, H2′,8), 2.04–1.90 (m, 1 H, H4), 1.69–
1.54 (m, 1 H, H3), 1.50–1.39 (m, 2 H, H4a,3′), 1.37, 1.36 (2 s,
6 H, CMe2), 1.31–1.20 (m, 1 H, H8′), 1.07–0.93 (m, 1 H, H4′),
0.88, 0.87 (2 s, 27 H, t-Bu), 0.08, 0.07, 0.03, 0.02 (s, 18 H,
SiMe2). 13C NMR: δ = 111.3 (CMe2), 84.2 (C6), 79.9 (C5),
70.3 (C7), 64.2 (CA), 61.4 (CB), 60.6 (CC), 59.2 (C8a), 48.1
(C2), 44.5 (C4a), 38.6 (C8), 28.5 (C3), 27.0 (CMe2), 25.9, 18.2
(t-Bu), 25.6 (C4), –4.4, –4.9, –5.3, –5.4, –5.6 (SiMe2).
HRMS (CI, CH4) calcd for C33H70NO5Si3 [M+ + 1]:
644.4562. Found: 644.4570.
(19) Typical Procedure for the Double Reductive Amination:
To a solution of ketoaldehyde 8 or 12 (387 µmol) in
methanol (1 mL), at 0 °C, were successively added sodium
cyanoborohydride (753 µmol, 1.9 equiv) and a mixture of
primary amine (387 µmol, 1 equiv) and HOAc (387 µmol, 1
equiv) in MeOH (400 µL). After 24 h stirring at 20 °C and
concentration in vacuo, a 10% aq solution of NaOH was
added and the mixture was extracted with CH2Cl2. The
combined organic layers were dried (anhyd Na2SO4),
filtered and concentrated in vacuo. Flash chromatography of
Synlett 2003, No. 3, 333–336 ISSN 0936-5214 © Thieme Stuttgart · New York