Synthesis of C2-symmetrical cyclic guanidino-sugars from D-mannitol

Article abstract of DOI:10.1055/s-1998-3129

An efficient method for the synthesis of C₂-symmetrical cyclic guanidino-sugars has been developed from 1,2:5,6-dianhydro-3,4-O-methylethylidene-D-mannitol or L-iditol.

Full text of DOI:10.1055/s-1998-3129

402
LETTERS
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Synthesis of C -Symmetrical Cyclic Guanidino-Sugars from D-Mannitol
2
Laurence Gauzy, Yves Le Merrer,* and Jean-Claude Depezay
Université René Descartes, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, associé au CNRS, 45, rue des Saints-Pères,
75270 Paris Cedex 06, France
Fax (33) 01 42 86 83 87; E-mail lemerrer@bisance.citi2.fr
Received 22 December 1997
Abstract : An efficient method for the synthesis of C -symmetrical
2
cyclic guanidino-sugars has been developed from 1,2:5,6-dianhydro-
3,4-O-methylethylidene-D-mannitol or L-iditol.
In recent years there has been much interest in the synthesis of different
analogues of sugars because of their potential activity as inhibitors of
glycosidases that are involved in various natural processes such as
1
diabetes or cancer.
Many polyhydroxylated pyrrolidines, piperidines and indolizidines
(azasugars) are compounds that have been shown to selectively inhibit
2
the oligosaccharide processing enzymes. More recently, cyclic
3
4
1,5
amidino, amidrazino or guanidino-sugars have been synthesized
because of their ability to mimic, in their protonated form, the partial
positive charge of the putative transition state for glycoside hydrolysis.
In this area, we wish to present preliminary results concerning the
Scheme 2
Thus, treatment of 1,2:5,6-dianhydro-3,4-O-methylethylidene-L-iditol
9 (or D-mannitol 10) by 1 equivalent of guanidine in refluxing ethanol in
the absence of any guanidinium salt (the free base is first generated from
synthesis of the new C -symmetrical polyhydroxylated cyclic
guanidines 1, 2, 3 and 4 (Scheme 1).
2
®
-
its hydrochloride salt on Amberlite IRA 400 (OH ) in ethanol) yields
10
directly the corresponding cyclic guanidine 11 (or 12) in 95% yield.
Removal of the acetonide group with aqueous trifluoroacetic acid, or
with hydrogen chloride in methanol afforded the C -symmetrical
2
11
12
guanidine 1 (or 2 ) which was isolated as its trifluoroacetate or
hydrochloride salt in 70% yield.
13
Even if the former works on N,N'-dialkylation of guanidine let us
think that the epoxides opening occurred with two different nitrogen
atoms of guanidine, none of the different analyses (NMR, MS, ...) could
prove this hypothesis. In order to justify the structure of compounds 1
and 2, we used another strategic approach, much longer but univocal,
involving the synthesis of a cyclic thiourea (Scheme 3).
Scheme 1
These compounds are analogues of the azepanes 5 and 6, and of the
pyrrolidines 7 (DMDP) and 8, respectively, that we previously obtained
from D-mannitol and that inhibit glycosidases in the low micromolar
6
range.
Formally, cyclic guanidine 1 (or 2) results from the N,N'-dialkylation of
guanidine by a C , C -diactivated derivative of L-iditol (or D-mannitol).
1
6
The first method we used (Scheme 2) consists of the nucleophilic
opening of L-iditol or D-mannitol bis-epoxide by guanidine and proved
to be very efficient to obtain enantiomerically pure cyclic guanidine 1 or
2.
Considering that ring opening of the bis-epoxides, in which the 3,4-diol
was protected as a dibenzyl ether, by an excess of guanidine in the
presence of guanidinium sulfate led to guanidinomethyl
7
polyhydroxylated tetrahydrofuran by O-cyclization and that the
The synthesis began with the diazido compound 13 obtained from bis-
protective group plays a decisive role in the selectivity of ring opening
of the bis-epoxide, we chose to protect the 3,4-diol as an acetonide, to
epoxide 9 by nucleophilic ring-opening with NaN (83%). Then
protection of the free hydroxyl groups of 13 by benzylation (NaH,
3
8
prevent O-cyclization. The bis-epoxides 9 and 10 are easily prepared
from D-mannitol.
PhCH Br, 89%), and subsequent heterogeneous catalytic reduction led
to the 1,6-diamine 15 (82%). Treatment of 15 with carbon disulfide in
2
9

April 1998
SYNLETT
403
14
pyridine yielded exclusively the thiourea 16 in almost quantitative
preparing various polyhydroxylated cyclic guanidines, and related
compounds.
yield, which can be easily transformed into the N-benzyl guanidine 17
by benzylamine in the presence of HgCl and triethylamine (94%).
15
2
After removal of all benzyl protecting groups by an excess of sodium in
Acknowledgements. We wish to thank the Drs D. Damour and S.
Mignani for helpful discussions, and Rhône-Poulenc Rorer for financial
support.
ammonia, the desired cyclic guanidine 1 was then isolated as its
®
-
trifluoroacetate salt after purification on Amberlite IRA 400 (OH ) and
deprotection of the acetonide group by warming of the resulting free
base with aqueous trifluoroacetic acid (57% overall yield from 17).
Similar reactions performed from the bis-epoxide 10 led to the
corresponding cyclic guanidine 2, isolated as its trifluoroacetate salt,
confirming its structure.
References and Notes
(1) Ganem, B. Acc. Chem. Res. 1996, 29, 340-347, and refs. therein.
(2) Karlsson, G.B.; Butters, T.D.; Dwek, R.A.; Platt, T.M. J. Biol.
Chem. 1993, 268, 570-576; Winchester, B.; Fleet, G.W.J.
Glycobiology, 1992, 2, 199-210.
Obtaining the cyclic guanidine 3 (or 4) required now formally the N,N'-
dialkylation of guanidine by a C , C -diactivated derivative of L-iditol
2
5
(3) Tong, M.K.; Papandreou; G.; Ganem, B. J. Am. Chem. Soc. 1990,
112, 6137-6139; Knapp, S.; Choe, Y.H.; Reilly, E. Tetrahedron
Lett. 1993, 34, 4443-4446; Blériot, Y.; Genre-Grandpierre, A.;
Tellier, C. Tetrahedron Lett. 1994, 35, 1687-1870; Blériot, Y.;
Dintinger, T.; Genre-Grandpierre, A.; Pradines, M.; Tellier, C.
Bioorg. Med. Chem. Lett. 1995, 5, 2655-2660; Suzuki, K.; Fujii,
T.; Sato, K.; Hashimoto, H. Tetrahedron Lett. 1996, 37, 5921-
5924.
(or D-mannitol). This was realized by a modification of the last method
(Scheme 4), by selective protection of the primary hydroxyl groups and
activation of the secondary ones. Thus, nucleophilic ring opening of bis-
epoxide 9 with sodium benzylate cleanly occurred to give the 1,6-di-O-
benzyl derivative 18 (57%), which was then converted routinely into the
2,5-dimesylate 19. However, attempts to achieve direct cyclization with
guanidine failed under different conditions. Nevertheless, nucleophilic
substitution of the 2,5-dimesylate 19 by sodium azide afforded the 2,5-
diazido derivative 20 (63% overall yield from 18) with inversion of
configuration at C and C . This latter, as above, was subjected
(4) Pan, Y.T.; Kaushal, G.P.; Papandreou, G.; Ganem, B.; Elbein,
A.D. J. Biol. Chem. 1992, 267, 8313-8318; Papandreou, G.; Tong,
M.K.; Ganem, B. J. Am. Chem. Soc. 1993, 115, 11682-11690.
2
5
successively to catalytic reduction of the azido groups into amines, then
cyclization into thiourea, transformation into N-benzyl guanidine 23,
(5) Chan, A.W.-Y.; Ganem, B. Tetrahedron Lett. 1995, 36, 811-814;
Jeong, J.-H.; Murray, B.W.; Takayama, S.; Wong, C.-H. J. Am.
Chem. Soc. 1996, 118, 4227-4234.
and subsequent removal of all protecting groups. The C -symmetrical
2
16
guanidine 3 was isolated as its trifluoroacetate salt in 40% overall
yield from 20. The same sequence of reactions carried out from the bis-
epoxide 10 afforded the corresponding cyclic guanidine 4, isolated as
its trifluoroacetate salt, in similar yields.
(6) Le Merrer, Y.; Poitout, L.; Depezay, J.-C.; Dosbaa, I.; Geoffroy,
17
S.; Foglietti, M-J. Bioorg. Med. Chem. 1997, 5, 519-533.
(7) Gravier-Pelletier, C.; Bourissou, D.; Le Merrer, Y.; Depezay, J.-
C. Synlett 1996, 3, 275-278.
(8) Poitout, L.; Le Merrer, Y.; Depezay, J.-C. Tetrahedron Lett. 1994,
35, 3293-3296; Poitout, L. Thesis, Université Pierre et Marie
Curie, Paris, 1995.
(9) Le Merrer, Y.; Duréault, A.; Greck; C.; Micas-Languin, D.;
Gravier, C.; Depezay, J.-C. Heterocyles 1987, 25, 541-547.
(10) Representative experimental procedure for the synthesis of 11 (or
12) : a solution of guanidine [generated from an ethanolic solution
of guanidinium hydrochloride (83 mg, 87 µmol) on Amberlite®
-
IRA 400 (OH )] and bis-epoxide 9 (or 10) (170 mg, 92 µmol) in
ethanol (1 mL) was refluxed for 1 h. After concentration under
reduced pressure, the crude cyclic guanidine was dissolved in
water, washed several times with CH Cl , and concentrated under
2
2
reduced pressure to give 208 mg of 11 (or 12) as a white
hygroscopic solid.
20
1
(11) Selected physical data of 1·TFA: [α]
+19 (c 0.25, H O);
H
C
D
2
13
NMR (250 MHz, D O) δ: 3.25-3.4(m, 2H), 3.45-4.1(m, 6H);
2
NMR (63 MHz, D O) δ: 54.7(C ), 74.2, 76.1(C
),
2
1,6
2,3,4,5
159.6(C
), 118.4(q, J 284 Hz, CF ), 164.4(q, J 37 Hz,
3 CF
The obtained cyclic guanidino-sugars 1, 2, 3 and 4 are currently being
evaluated as inhibitors of different glycosidases, and the results will be
reported elsewhere.
guanidine
-
CO ).
2
20
1
(12) Selected physical data of 2·HCl: [α]
+5 (c 0.75, H O); H
2
D
NMR (250 MHz, D O) δ: 3.35-3.5(m, 2H, H ), 3.6-3.75(m, 2H,
2
2,5
In summary, this study indicated an efficient synthetic pathway to
construct polyhydroxylated cyclic guanidines. The first method
described involves direct opening of a bis-epoxide by free guanidine,
whereas for the second one, the N,N’-dialkylation of guanidine was
performed via a cyclic thiourea. An important feature of this last
methodology is an ability to introduce, in place of benzylamine used
during the transformation of cyclic thiourea into guanidine, other
amines with the goal of obtaining novel glycomimetic oligomers. Our
current efforts involve the development of new synthetic methods of
13
H
), 3.75-4.05(m, 4H, H ); C NMR (63 MHz, D O) δ:
1,6 2
3,4
+
47.9(C ), 71.6, 72.2(C
for C H O N : (MH ) calcd 206.1141, found 206.1118.
), 160.4(C
); HMRS (FAB )
1,6
2,3,4,5
guanidine
+
7
16 4 3
(13) Hebrard, P.; Olomucki, M. Bull. Soc. Chim. Fr. 1970, 5, 1938-
1942; Fritsche-Lang, W.; Wilharm, P.; Hädicke, E.; Fritz, H.;
Prinzbach, H. Chem. Ber. 1985, 118, 2044-2078.
(14) Allen, C.F.H.; Edens, C.O.; VanAllan, J. Org. Synth. 1995,
Collected Vol III, 394-395.

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LETTERS
SYNLETT
(15) For other examples of transformation of cyclic thiourea into
guanidine, see: Ramadas, K.; Srinivasan, Tetrahedron Lett. 1995,
36, 2841-2844; Jadhav, P.K.; Woerner, F.J.; Man, H-W. Bioorg.
Med. Chem. Lett. 1997, 7, 2145-2148; for examples of
transformation of N-substituted thiourea with electron-
withdrawing group into guanidine, see: Atwall, K.S.; Ahmed,
S.Z.; O'Reilly, B.C. Tetrahedron Lett. 1989, 30, 7313-7316; Poos,
M.A.; Iwanowicz, E.; Reide, J.A.; Lin, J.; Gu, Z. Tetrahedron
Lett. 1992, 33, 5933-5936; Kim, K.S.; Qian, L. Tetrahedron Lett.
1993, 34, 7677-7680, and refs. therein.
3.9-4.1(part AB of ABX, 4H, J 12 Hz, J 3.6 Hz, J 6.4 Hz,
AB AX BX
13
H
); C NMR (63 MHz, D O) δ: 60.7(C ), 63.2(C ),
2 2,5 1,6
1,1’,6,6’
-
75.3(C ), 119.3(q, J 288 Hz, CF ), 166.1(q, J 23 Hz, CO );
HMRS (FAB ) for C H O N : (MH ) calcd 206.1141, found
3,4
3
CF
2
+
+
7
16 4 3
206.1095.
20
1
(17) Selected physical data of 4·TFA: [α]
+12 (c 0.95, H O);
H
D
2
13
NMR (250 MHz, D O) δ: 3.65-4.1(m); C NMR (63 MHz, D O)
2
2
δ: 59.6(C ), 63.9(C ), 72.3(C ), 119.3(q, J 291 Hz, CF ),
2,5
1,6
3,4
3
-
+
160.6(C
), 166.1(q, J 23 Hz, CO ); HMRS (FAB ) for
CF 2
guanidine
+
C H O N : (MH ) calcd 206.1141, found 206.1165.
7
16 4 3
20
1
(16) Selected physical data of 3·TFA: [α]
+8 (c 1.3, H O); H NMR
2
D
(250 MHz, D O) δ: 3.4-3.5(m, 2H, H ), 3.6-3.7 (m, 2H, H ),
2
2,5
3,4