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Efficient, stereoselective synthesis of 4-E- and 4-Z-D-erythro-sphingenines having C16, C18, and C20 carbon-chains was achieved in 13 steps, starting from allyl 2-benzyloxycarbonylamino-2-deoxy-alpha-D-glucopyranoside. 2-Amino-1,6-di-O-tert- butyldiphenylsilyl-2-N,3-O-carbonyl-2-deoxy-D -allitol was used as the key intermediate.
The synthesis is described of highly acid-sensitive, 1,1-dialkyl-1-methoxymethyl glucosides (acetal-glucosides) as potential anti-cancer prodrugs. Reaction of 2,3,4,6-tetra-O-acetyl-1-O-trimethylsilyl-beta-D-glucopyranose (4) severally with various aliphatic and alicyclic ketones and methyl trimethylsilyl ether, in the presence of catalytic amounts of trimethylsilyl trifluoromethanesulfonate, afforded the corresponding acetylated acetal-beta-glucosides, e.g., acetone gave 1-methoxy-1-methylethyl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (7a). Likewise the alpha-anomer (8a) of 7a was obtained from the alpha-anomer of 4. Deacetylation of the tetra-acetates then gave the acetal-alpha- and -beta-glucosides.
Bromoacetylation of methyl beta-D-galacto- (1), alpha-D-galacto- (6), beta-D-gluco- (18), (22), and alpha-D-manno-pyranoside (31), and benzyl beta-D-glucopyranoside (27), gave the corresponding 6-O-bromoacetyl derivatives 2, 7, 19, 23, 32, and 28 in 50-60% yields. Bromoacetylation of methyl 3-O-benzyl-beta-D-galactopyranoside (11) afforded methyl 3-O-benzyl-6-O-bromoacetyl-beta-D-galactopyranoside (12, 60%) as well as methyl 3-O-benzyl-2,6-di-O-bromoacetyl-beta-D-galactopyranoside (13, 14%). Compounds 2, 7, 19, 23, 32, 28, and 12 were benzoylated and the fully protected derivatives obtained were dehaloacetylated with thiourea to afford the methyl 2,3,4-tri-O-benzoyl-D-glycopyranosides of beta-galactose (5), alpha-galactose (9), beta-glucose (21), alpha-glucose (25), and alpha-mannose (34), as well as benzyl 2,3,4-tri-O-benzoyl-beta-D-glucopyranoside (30) and methyl 3-O-benzyl-2,4-di-O-benzoyl-beta-D-galactopyranoside (15). These compounds can be used as nucleophiles for the synthesis of (1----6)-linked oligosaccharides. The conversion 1----5 could be performed without isolation of the intermediates. The treatment of bromoacetyl derivatives with benzoyl chloride in pyridine resulted in the benzoylation of the remaining free hydroxyl groups and the simultaneous substitution of bromine by chlorine, yielding the corresponding mono-O-chloroacetyl derivatives. Benzoylations with benzoyl bromide avoided this secondary event. Glycosyl donors differentially substituted to allow further extension of the oligosaccharide chain at position 6 of D-glucose, D-galactose, and D-mannose, and sequentially at positions 6 and 3 in the case of the D-galactosyl donor derived from 15, were readily obtained by treatment of the appropriate, fully protected methyl glycosides with 1,1-dichloromethyl methyl ether in the presence of a catalytic amount of zinc chloride.
6-Deoxy-6-mycoloylamino-alpha,alpha-trehalose, a biologically active derivative of 6,6'-di-O-mycoloyl-alpha,alpha-trehalose (TDM), and N-acetyl-6-O-(aminoacyl)-muramoyl dipeptide (MDP) were joined chemically by a succinic acid unit. The compounds synthesized showed activities that are characteristics of both TDM and MDP.
In attempting to synthesize the analogue of beta-Kdo (2R)-2-carboxy-6-(1',2'-dihydroxyethyl)-4,5-dihydroxy-D-manno-1,2 lambda 5-oxaphosphorinan-2-one (6) as an inhibitor of the enzyme CMP-Kdo synthetase, which is involved in the biosynthesis of the lipopolysaccharide component of the outer membrane of Gram-negative bacteria, (2R)-6-(1',2'-dihydroxyethyl)-2-ethoxy-3,4,5-trihydroxy-4,5:1', 2'-di-O-isopropylidene-D-glycero-D-talo-1,2 lambda 5-oxaphosphorinan-2-one (8) was converted into (2S)-6-(1',2'-dihydroxyethyl)-4,5-dihydroxy-4,5:1',2'-di-O-isop rop ylidene-2-vinyl-D-manno-1,2 lambda 5-oxaphosphorinan-2-one (16), but alkene cleavage to give the target carboxyphosphonate failed. Reduction-oxidation-Arbuzov reaction on the intermediate (2R)-6-(1',2'-dihydroxyethyl)-2-ethoxy-4,5-dihydroxy-4,5:1', 2'-di-O-isopropylidene-D-manno-1,2 lambda 5-oxaphosphorinan-2-one (11) gave the 2S isomer of the protected target compound, but removal of the protecting groups gave the acyclic product dilithium (D-manno-2,3,4,5,6-pentahydroxyhexyl)phosphinatoformate (24). N.m.r. studies of the intermediates allowed assignment of stereochemistry at P for all compounds via 2JP,H coupling constants.
"Dihydroacarbose" (2), an alpha-D-glucosidase inhibitor having a pseudo-tetrasaccharide structure, was synthesized by reductive coupling of 4(3)-amino-1(1),6(1)-anhydro-2(1),3(1),2(2),3(2),6(2),2(3),3(3)-hepta-O- benzyl-4(3),6(3)-dideoxy-beta-maltotriose and 2D-(2,4/3,5)-2,3,4-tris(benzyloxy)-5-(trityloxymethyl)cyclohexa non e with sodium-cyanoborohydride. The former intermediate was prepared from a partially benzylated 1(1),6(1)-anhydro-beta-maltotriose, and the latter was prepared from a chiral, penta-substituted cyclohexene derived from D-glucose. The synthetic 2 was found to be a strong, non-competitive inhibitor (Ki = 1.13 x 10(-6) M) against small-intestinal sucrase of rat.
N-Phthaloylation of lactosamine gave various glycosyl donors (beta-chloride, beta-trichloroacetimidate) and glycosyl acceptors (3',4'-diol). Coupling of the chloride with a methyl beta-D-glycoside led to the tetrasaccharide fragment, beta-D-Galp-(1----4)-beta-D-GlcpNac-(1----3)-beta-D-Galp-(1----4)- beta-D-GlcpNAcOMe. Acetolysis of the protected tetrasaccharide, followed by treatment with hydrogen chloride, gave a tetrasaccharide chloride which was coupled with the methyl beta-glycoside of lactosamine. A hexasaccharide fragment, [beta-D-Galp-(1----4)-beta-D-GlcpNAc-(1----3)]2-beta-D-Galp-(1----4)-bet a- D-GlcpNAcOMe, was thus obtained by this ("n + 1") method. A more efficient ("n + n") method was applied for the synthesis of an octasaccharide fragment, [beta-D-Galp-(1----4)-beta-D-GlcpNAc-(1----3)]3-beta-D-Galp- (1----4)-beta-D-GlcpNAcOMe (38), where di- and tetra-saccharide intermediates having a 3,4-O-isopropylidene-beta-D-galactopyranosyl nonreducing terminal group and a benzyl beta-D-glycoside group were precursors, either as glycosyl donors (beta-trichloroacetimidates) or glycosyl acceptors (3,4-diols as nonreducing terminal groups). Thus, doubling the length of the repetitive oligosaccharide sequence could be efficiently accomplished at each glycosylation step.
Methyl 3,4,6-tri-O-benzyl-beta-D-mannopyranoside (2), methyl 2,3-O-isopropylidene-beta-D-mannopyranoside (11), and 4-nitrophenyl 2,3-O-isopropylidene-beta-D-mannopyranoside (12) were each condensed with 2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl bromide (1) in the presence of mercuric cyanide, to give after deprotection, methyl 2-(5) and 6-O-alpha-D-mannopyranosyl-beta-D-mannopyranoside (15), and 4-nitrophenyl 6-O-alpha-D-mannopyranosyl-beta-D-mannopyranoside (20), respectively. A similar condensation of 11 with 3,4,6-tri-O-acetyl-2-O-(2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl)-a lpha-D- mannopyranosyl bromide (21) and 2,3,4-tri-O-acetyl-6-O-(2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl)-a lpha D-mannopyranosyl bromide (25), followed by removal of protecting groups, afforded methyl O-alpha-D-mannopyranosyl-(1----2)-O-alpha-D-mannopyranosyl-(1----6)-beta -D- mannopyranoside (24) and methyl O-alpha-D-mannopyranosyl-(1----6)-O-alpha-D-mannopyranosyl-(1----6)-beta -D- mannopyranoside (28), respectively. Bromide 25 was also condensed with 12 to give a trisaccharide derivative which was deprotected to furnish 4-nitrophenyl O-alpha-D-mannopyranosyl-(1----6)-alpha-D-mannopyranosyl-(1----6)-beta-D - mannopyranoside (31). Phosphorylation of methyl 3,4,6-tri-O-benzyl-2-O-alpha-D-mannopyranosyl-beta-D-mannopyranoside and 15 with diphenyl phosphorochloridate in pyridine gave the 6'-phosphates 6 and 16, respectively. Hydrogenolysis of the benzyl and phenyl groups provided methyl 2-O-(disodium alpha-D-mannopyranosyl 6-phosphate)-beta-D-mannopyranoside (7) and methyl 6-O-(disodium alpha-D-mannopyranosyl 6-phosphate)-beta-D-mannopyranoside (17) after treatment with Amberlite IR-120 (Na+) cation-exchange resin. The structures of compounds 5, 7, 15, 17, 20, 24, 28, and 31 were established by 13C-n.m.r. spectroscopy.
O-alpha-D-Glucopyranosyl-(1----6)-O-beta-D-glucopyranosyl-(1----6)-1-N- [L-aspart-1-oyl-(L-proline)-4-oyl]-alpha- and -beta-D-glucopyranosylamine have been prepared, as models for a derivative possibly present in the glomerular basement membrane of rats, by condensation of the corresponding D-glucosyl-dipeptide derivatives with 2,3,4,2',3',4',6'-hepta-O-acetyl-alpha-D-isomaltopyranosyl bromide in the presence of mercuric cyanide, followed by deprotection of the trisaccharide-dipeptide derivatives.
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Synthesis of 3-O-acetyl-2-benzyloxycarbonylamino-2-deoxy-4,6-O-ethylidene- alpha-(7 alpha) and-beta-D-glucopyranose (7 beta) and their 3-O-chloroacetyl analogues (11 alpha and 11 beta) are described. Condensation (BF3-etherate, ethyl acetate, -20 degrees) of 7 alpha with 4'-O-benzyloxycarbonyl-4'-O-demethyl-4-epipodophyllotoxin (8) afforded mainly the beta-glycoside 9 beta (alpha, beta-ratio 1:9). Condensation of 11 alpha beta with 8 or the 4'-O-chloroacetyl analogue 13 gave mainly the 4-O-(2-benzyloxycarbonylamino-3-O-chloroacetyl-2-deoxy-4,6-O-ethyl idene-beta-D- glucopyranosyl)-epipodophyllotoxin 12 beta or 15 beta. Glycosidation of podophyllotoxin (14) with 11 alpha beta (during which the aglycon epimerized at C-4 under the action of BF3-etherate) afforded alpha- (16 alpha) and beta-glycoside (16 beta) in the ratio 1:5. Removal of the chloroacetyl groups from 12 beta, its alpha analogue 12 alpha, and 15 beta gave the 4-O-(2-benzyloxycarbonylamino-2-deoxy-4,6-O-ethylidene-alpha-(17 alpha) and -beta-D-glucopyranosyl)-4'-O-demethyl-epipodophyllotoxins (17 beta and 20 beta), respectively. Hydrogenolysis of the benzyloxycarbonyl groups then gave 4-O-(2-amino-2-deoxy-4,6-O-ethylidene-alpha- (18 alpha) and -beta-D-glucopyranosyl)-4'-O-demethyl-4-epipodophyllotoxin (18 beta). Reductive alkylation of 18 beta and 18 alpha afforded the 2"-deoxy-2"-dimethylamino-etoposide 3 and its alpha analogue 19 alpha.
The development and execution of the first examples of a new and general approach to carbocyclic analogs of carbohydrates ("pseudo-sugars") is presented. Complete experimental details for the preparation of the carbocyclic analog of beta-D-fructofuranose 6-phosphate are described for the first time. In the conclusion, the success of the synthetic strategy is analyzed and an approach to retrosynthetic analysis based on "unitive synthons" is offered for consideration.
The temperature dependences of the transverse (R2) and longitudinal (R1) n.m.r. relaxation rates of 87Rb+ in aqueous 5% iota-carrageenan have been compared with similar data for a sample purified by treatment with kappa-carrageenase. In each sample, the relaxation rates were sensitive to the conformation (helix or random coil). In the intact sample, the small (less than or equal to 5%) fraction of kappa-carrageenan (which, in its helical state, specifically binds rubidium ions) was solely responsible for the pronounced line-broadening that has been observed hitherto for 87Rb in iota-carrageenan gels. In the purified sample, the effects on the relaxation of 87Rb induced by iota-carrageenan are similar to those found in comparable systems in the absence of site-binding of the ions. Thus, there was a modest enhancement of the relaxation with R1 approximately R2 for the flexible coil conformation and a comparably larger effect, with significant contributions from dynamic processes on the time-scale of the inverse resonance frequency or longer, for the thicker, more highly charged and rigid helix conformation of iota-carrageenan.
The conformation of 1,6-anhydrolactoase (1) has been investigated by n.m.r. spectroscopy and molecular mechanics calculations. For a solution in D2O, the 1,6-anhydroglucopyranoid ring has a 1C4 conformation, whereas there is a approximately 1:1 equilibrium between the 1C4 and the BO,3 conformations in (CD3)2SO. There is restricted flexibility with phi -80 +/- 20 degrees and psi -120 +/- 40 degrees. The hexa-acetate (2) of 1 shows a similar conformational behaviour.
The solution salts of the 6'-sulfate 12, the 4'-sulfate 15 and the 4',6'-disulfate 17 of benzyl 4-O-(beta-D-galactopyranosyl)-beta-D-glucopyranosiduronate 10 have been synthesized. Methyl [benzyl 2,3-di-O-benzoyl-4-O-(2,3-di-O-benzoyl-beta-D-galactopyranosyl)-beta-D-+ ++glucopyranosid]uronate (9) has been prepared as a key intermediate from benzyl 4',6'-O-benzylidene-beta-D-lactopyranoside (2). Protection of 2 at C-6 with the tert-butyldimethylsilyl group, followed by O-perbenzoylation and disilylation, gave benzyl 2,3-di-O-benzoyl-4-O-(2,3-di-O-benzoyl-4,6-O-benzylidene-beta-D-galac top yranosyl)-beta-D-glucopyranoside (7). Oxidation of the 6-position of 7 proved to be difficult. However, 7 could be converted into the tert-butyl glucuronate 8 using chromium trioxide-pyridine and tert-butanol. Simultaneous hydrolysis of the benzylidene acetal and the tert-butyl ester groups, followed by esterification of the resulting free acid with diazomethane, yielded 9. Compound was directly sulfated with sulfur trioxide-trimethylamine within 12 h to give the 6'-sulfate 11. The 4',6-disulfate 16 was accessible by running the reaction under the same conditions for 14 days. The 4'-sulfate 14 was obtained after protecting the 6'-OH group of 9 with benzoyl cyanide to give the 6'-benzoate 13 followed by sulfation under more vigorous reaction conditions. Deesterification of 9, 11, 14, and 16 was achieved by treatment with aqueous sodium hydroxide in tetrahydrofuran to give 10, 12, 15, and 17, respectively.
Deacetylation of octa-O-acetylsucrose (1) with Alcalase or protease N gave the 2,3,4,6,3',4',6'-hepta-acetate (2) as the initial major product with the 2,3,4,6,3',4'-hexa-acetate (3) as the subsequent main product. The 2,3,4,1',3',4',6'-hepta-acetate (5) was obtained from 1 by the action of lipase OF or lipase AP6, and the 2,3,4,6,1',3',6'-(4) and 2,3,4,6,1',3',4'-hepta-acetate (7) by the action of Candida lipase and chymotrypsin, respectively. The 2,3,6,1',3',4',6'-hepta-acetate (6) was formed from 5 by acyl migration.
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