Tetrahedron Letters Tetrahedron Letters 45 (2004) 8043–8046
Synthesis of C8-glycomimetics as potential glycosidases inhibitors Olivia Andriuzzi, Christine Gravier-Pelletier* and Yves Le Merrer* Universite´ Rene´ Descartes, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, 45, rue des Saints-Pe`res, 75270 Paris Cedex 06, France Received 28 June 2004; revised 30 August 2004; accepted 31 August 2004 Available online 17 September 2004
Abstract—The synthesis of C8-glycomimetics is described from C2-symmetrical polyhydroxylated cyclooctenes derived from carbocyclisation of enantiomerically pure 1,9-dienes by ring closing metathesis. Their obtention notably involved either hydroboration followed by oxidation to carbasugars or to cyclooctanones then reductive amination, or formation of a cis-cyclic sulfate followed by successive introduction of an azido group, reduction and subsequent reductive amination. The biological activity of the C8-carbasugars and related aminocyclitols, analogous to voglibose, has been evaluated towards several commercially available glycosidases. Ó 2004 Elsevier Ltd. All rights reserved.
Glycosidases, enzymes responsible for the formation and the cleavage of glycosidic bonds, are involved in numerous biological processes such as the catabolism of glycoconjugates or the degradation of polysaccharides. Their inhibition therefore displays diverse therapeutical applications such as diabetes1 and cancer,2 thus glycosidases inhibitors with various structures, iminosugars or aminocyclitols3 and carbasugars4 have been highlighted (Fig. 1). Among them, miglitol (GlysetÒ)5 and voglibose (BasenÒ)6 are used in non-insulino dependant diabetes treatment. As part of a programme aimed at the synthesis of potential glycosidases inhibitors,7 we focused on the access to eight-membered carbasugars and related aminocyclitols to study the effect of the enhanced flexibility and of the new spatial distribution of the hydroxyl groups displayed by these structures on their adaptability in the active site of the enzyme. The versatile described approach allows access to various configurations at chiral centres. Furthermore, in order to mimic the aglycon part encountered, for example, in voglibose, alkylation of the amine functionality can also be carried out. The retrosynthesis of the targeted compounds (Fig. 2) relies
Keywords: Glycomimetics; Aminocyclitols; Carbasugars; Cyclic sulfate; Reductive amination. * Corresponding authors. Tel.: +33 (0)142862181; fax: +33 (0)14286 8387 (C.G.-P.); tel.: +33 (0)142862176; fax: +33 (0)142868387 (Y.L.M.); e-mail addresses:
[email protected];
[email protected] 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.08.172
OH
OH
HO
HO
OH
HO
N R
HO
Miglitol : R = CH2CH2OH HO
NH
HO
DNJ : R = H
HO
OH
HO
Voglibose
OH OH
HO HO
NHR C7-aminocyclitol
OH
HO H OH
HO H OH
OH OH
Bicyclic carbasugar
R = H, CH(CH2OH)2
Figure 1. Examples of a-D -glucosidase inhibitors.
on a strategy we recently reported,8 based on a key step of carbocyclisation by ring closing metathesis involving a 1,9-diene, easily available from the C2-symmetrical D manno- or L -ido-bis-epoxide. The synthetic potentialities of the newly created double bond in the cyclooctenic structure were then explored to reach the targeted glycomimetics. For this purpose, the most straightforward approach to the C8-aminocyclitols unsubstituted in the C2-position (A = H) seemed to be a double bond hydroboration followed by oxidation or aminolysis, whereas to the C8-aminocyclitols hydroxylated in the C2-position
8044
O. Andriuzzi et al. / Tetrahedron Letters 45 (2004) 8043–8046 HO HO
OH OH *
*
O
O
*
*
In order to reach the corresponding aminocyclitols, we turned to the hydroboration of 1 or 2 followed by aminolysis with sulfamic acid,12 however this reaction revealed unsuccessful. Alternative activation of the alcohol function as its triflate (Tf2O, 2,6-lutidine, CH2Cl2, 78 °C) followed by treatment with NaN3 or ethanolamine (DMF, 78 °C to rt) led to recover the initial cyclooctene as a result of b elimination.
OP
PO
* * A
P = TBDMS
B
A = H, B = OH or NHR A = OH, B = OH or NHR
O
1 : D-manno 2 : L-ido
O
O *
* O
D-manno L-ido
O
O
*
*
Nevertheless, the targeted compounds could be efficiently obtained through oxidation of the precedent mixture 3a and 3b followed by reductive amination (Scheme 2).
OH
HO
D-manno L-ido
Figure 2. Retrosynthetic analysis.
(A = OH) it seemed to be an epoxidation followed by the nucleophilic opening of the epoxide moiety by a primary amine or another nitrogen nucleophile. Accordingly, treatment of the O-protected polyhydroxylated cyclooctene 1 in diethyl ether by borane–tetrahydrofuran complex9 was followed by oxidative cleavage with alkaline hydrogen peroxide (Scheme 1). The mixture of the two epimers 3a and 3b in a 2/1 ratio10 was isolated in 74% yield, and each isomer was isolated as a pure compound11 by flash chromatography. The structure of the major isomer 3a was unambiguously assigned by 2D-NMR studies. This structure is in agreement with the hydroboration of the double bond opposite to the tert-butyldimethylsilyloxy group in b position. Acidic hydrolysis (TFA/H2O) of each compound, 3a and 3b, afforded the corresponding C8-carbasugars 5a and 5b. In the same manner, hydroboration of the L -ido-cyclooctene 2 gave the protected cyclitols 4a and 4b in 88% yield. However, in that case the diastereoselectivity decreased (3/2) and mainly led to an hydroboration on the same side as the tert-butyldimethylsilyloxy group in b position. As above, acidic hydrolysis of 4a and 4b cleanly led to the deprotected C8-carbasugars 6a and 6b.
O
P2O
O
PO
OP
a
P1O
OP2 OP1
P2O P1O
PO
3a : P1 = TBDMS, P2 = Me2C : 3b : 5b 5a : P1 = P2 = H
P2O P O
O
1
a
P2O P O
OP2 OP1
1
OP2 OP1
+
88%
OH 2
1
O
SiO
O OSi
b
O OSi
b
Scheme 1. Reagents and conditions: (a) i. BH3ÆTHF, Et2O, ii. NaOH, H2O2; (b) TFA, H2O.
c
OH 1
7
NHR
O 2
O
O
SiO
OSi
b
SiO
NHR 1S/1R : 4/1 13 : R = CH2CH2OH 14 : R = CH(CH2OH)2
9 : R = CH2CH2OH 11 : R = CH(CH2OSi)2
Si = TBDMS
a
OH
HO
86%
HO
O OSi
96%
OH OH
HO c 1
NH
NH
O
OH
4a : P1 = TBDMS, P2 = Me2C : 4b 6a : P1 = P2 = H : 6b
HO
SiO
O
b
OP
OP1
a
OH
OH
O
O
OP2
+
74%
1
Thus, hydroboration of 1 and alkaline hydrogen peroxide treatment as above, followed by oxidation with pyridinium chlorochromate efficiently led to the corresponding fully O-protected polyhydroxylated cyclooctanone 7 in 86% overall yield. Reductive amination13 of 7 by ethanolamine in the presence of titanium(IV) tetraisopropoxide followed by the cyanoborohydride reduction of the imine intermediate gave the expected N-substituted derivative 9 displaying the aglycon part of miglitol. In the same way, the reductive amination was carried out with the bis-O-tert-butyldimethylsilylserinol14 to introduce the aglycon part of voglibose, and afforded the corresponding compound 11. Acidic hydrolysis of 9 and 11 gave, after purification by ion-exchange chromatography, the expected glycomimetics 13 and 14 in 60% and 63% overall yield, respectively. 1H NMR studies (500 MHz) revealed that 13 and 14 were mixtures of epimers in a 4/1 ratio.15 The absolute configuration at the newly created chiral centre for the major stereoisomer is the same as for the previous hydroboration reaction (1 ! 3a, 3b). Starting from the L -ido-cyclooctene 2, the ketone 8 was obtained in 96% yield as previously described, and subsequent reductive amination with ethanolamine was followed by acidic hydrolysis to afford the miglitol mimetic 12. This aminocyclitol isolated in 45% overall yield was also identified by 1H NMR (500 MHz) as a mixture of epimers in a 3/1 ratio
OH 8
10
OH 12 1S/1R : 3/1
Scheme 2. Reagents and conditions: (a) i. BH3ÆTHF, Et2O, ii. NaOH, H2O2, iii. PCC; (b) H2NCH2CH2OH or H2NCH(CH2OTBDMS)2, Ti(Oi-Pr)4, NaBH3CN, CH2Cl2; (c) TFA, H2O.
O. Andriuzzi et al. / Tetrahedron Letters 45 (2004) 8043–8046
in favour of the 1S stereoisomer, as for hydroboration (2 ! 4a, 4b). Now, to reach the 2-hydroxylated glycomimetics (A = OH) we turned to the epoxidation16 of cyclooctenes 1 and 2 (Scheme 3) by meta-chloroperbenzoic acid in the presence of sodium hydrogenocarbonate, which efficiently afforded the epoxides 15 and 1617 in 66% and 88% yield, respectively. Surprisingly, all attempts involving various nucleophiles (sodium azide, benzylamine, n-butylamine or serinol), and different experimental conditions (protic or aprotic solvent, presence or absence of a Lewis acid catalyst such as ytterbium triflate) to open the epoxide ring revealed unsuccessful, only leading to recover the starting material. To overcome this difficulty, we turned to a more electrophilic sulfate moiety18 (Scheme 4). So, syn-dihydroxylation19 of cyclooctenes 1 and 2 by a 5 mol % aqueous solution of osmium(IV) tetroxide in acetone in the presence of N-methylmorpholine oxide and tert-butanol cleanly led to the expected cis-diols 17 and 18.17 On the first hand, acidic hydrolysis of the O-protective groups furnished the expected cyclooctanic carbasugars 19 and 20. On the other hand, treatment of these diols 17 and 18 with thionyl chloride in the presence of triethylamine followed by subsequent oxidation with sodium periodate in the presence of ruthenium trichloride gave the cyclic sulfates 21 and 22. As expected, nucleophilic opening of the cyclic sulfate moiety was efficiently carried out by sodium azide in DMF at 80 °C,20 and was followed by acidic hydrolysis of the resulting acyclic sulfate ester to afford the respective azido-alcohol 23 and 24, isolated as a single stereoisomer in excellent yield (P95%). However, it has to be pointed out that more hindered nucleophiles, such as primary amines, revealed unable to open the sulfate 21 or 22. Next, reduction of each azido-alcohol 23 and 24 by dihydrogen in the presence of palladium black in ethyl acetate led to the corresponding amines 25 and 26. Acidic hydrolysis of the O-protective groups on the cyclooctylamines 25 and 26 by aqueous trifluoroacetic acid furnished, after purification by ionexchange chromatography, the targeted C8-glycomimet-
O
O
PO 1
OP
P = TBDMS
a 66%
O 15
PO b
O
O
*
*
OP * *
O PO
O
HO OP
2 a
A
A = N3, NHR
88%
O 16
Scheme 3. Reagents and conditions: (a) m-CPBA, NaHCO3, CH2Cl2; (b) NaN3 or PhCH2NH2, n-BuNH2 or serinol in protic or aprotic solvent.
1
1
P O
OP
2
O 2
P O
a
1
8045
OP
c
97%
O OSi
OH
1
P O P O
O S O O 21
OP1
2
1
OP
OP1
OP
2
OP
58% from 23
HO
1
NH2
OP
29 : P1 = Me2C, P2 = Si 31 : P1 = P2 = H, 50%
2
P1O 2 P O
a
OP1 2 OP
HO
O
OSi
1
P O P O
O S O O 22
1
P1O P O
OP
2
2
OP
f
HO
1
OP 1
OSi
HO
N3 24
OP1 2 OP
e
45% from 24
OP1 HO HN
O
SiO
d 95%
O 2
18 : P = Me2C, P = Si 20 : P1 = P2 = H, 91%
2
b
O
O
SiO
c
OH
1
b
1 2 25 : P = Me2C, P = Si 1 2 27 : P = P = H, 66% from 23
b
100%
92%
e
1
P O P O
f
N3 23
2
2
HO HN b
OSi
HO
O
17 : P1 = Me2C, P2 = Si 1 2 19 : P = P = H, 91%
O
SiO
d 98%
80%
HO b
O
SiO
1
2
30 : P = Me2C, P = Si 32 : P1 = P2 = H, 100%
b
NH2 2
26 : P = Me2C, P = Si 28 : P1 = P2 = H, 91% from 24
Si = TBDMS
Scheme 4. Reagents and conditions: (a) OsO4 5 mol %, NMO, acetone/ tert-BuOH; (b) TFA/H2O; (c) i. SOCl2, Et3N, CH2Cl2, ii. NaIO4, RuCl3, CH3CN/CCl4/H2O; (d) i. NaN3, DMF, 80 °C, ii. H2SO4, H2O/ THF; (e) H2, Pd black, EtOAc; (f) i. O@C(CH2O)2CMe2, Ti(Oi-Pr)4, ii. NaBH3CN, EtOH.
ics 27 and 28 with a free amine functionality. Alternatively, to obtain analogues of voglibose, the amine function of 25 and 26 could be alkylated via reductive amination13 with a dihydroxyacetone derivative. Thus, treatment of the amines 25 and 26 by the commercially available 2,2-dimethyl-1,3-dioxan-5-one in the presence of titanium(IV) tetra-isopropoxide followed by the cyanoborohydride reduction of the imine intermediate gave the expected N-alkylated derivatives 29 and 30. Then, simultaneous acidic hydrolysis of all protective groups led to the C8-voglibose mimetics 31 and 32. The biological activity of carbasugars 5a, 5b, 6a, 6b, 19 and 20, and unsubstituted or N-substituted aminocyclitols 12, 13, 14, 27, 28, 31 and 32 was evaluated at 1 mM concentration, as previously described,21 towards four commercially available glycosidases: a-D -glucosidase from Bacillus stearothermophilus, b-D -glucosidase from almonds, a-D -mannosidase from Jack beans and a-L -fucosidase from bovine kidney. Each of these new compounds revealed a poor inhibitor of the tested enzymes (
