Novel Chiral Glycerol Analogues Building Blocks. Application to the Synthesis of Bioactive Glycoglycerolipid Analogues

Abstract

Monoacylglycosylglycerols show anti-tumor promoting effects: in order to study the role of the ester function we have prepared by simple methods (R)-1-O-benzyl-1,2-decandiol, (R)-3-Obenzyl-1-O-hexyl-sn-glycerol, and (R)-1-O-benzyl-5-oxo-1,2-decandiol; these optically active compounds are building blocks for the synthesis of monohexanoylglycosylglycerol isosters.Monoacylglycosylglycerols have been reported to have significant anti-tumor promoting effects; 1 in particular, among the different derivatives, compounds 1b and 1c, both bearing a hexanoyl chain on the glycerol C-1, are the most active. 2,3 In the course of a project aimed at ascertaining the structural features responsible for the cancer chemopreventing activity, in order to study the role of the ester function in modulating this activity, we have planned to prepare the acylglucosyl-and galactosylglycerol analogues 2b-c, 3b-c and 4b-c in which the chain is linked to the glycosylglycerol skeleton through bonds metabolically more stable than the ester linkage.In this paper, the preparation of compounds 7, 8 and 9, suitably protected at the primary hydroxy group, i.e. the proper isosters of 1-O-hexanoyl-sn-glycerol 1a, which are required for the synthesis of the target compounds by glycosidation at the secondary hydroxyl, is described.To obtain the compounds with the desired C-2 configuration, the commercially available (R)-benzylglycydol 5 and (R)-g-hydroxymethyl-g-butyrolactone 6 were chosen as starting material for the synthesis of alkyl and ether isosters 2a and 3a or of the carbonylic isoster 4a, respectively.(R)-1-O-Benzyldecan-1,2-diol 4 7 was obtained in 80% yield from 5 by reaction with 1-heptylmagnesiumbromide and copper (I) bromide-dimethyl sulfide complex; the same protected epoxyalcohol 5 afforded the desired (R)-hexylether 5 8 (70% yield) by reaction with sodium in hexanol (Scheme 1). 6 Scheme 1In turn, for the synthesis of isoster 9, (R)-lactone 6, after reaction with benzyl trichloroacetimidate to the corresponding benzylether 7 10, was converted into its methyl ester and protected as silylether giving compound 11. 8 LiAlH 4 reduction of the ester function, followed by pyridium chlorochromate (PCC) oxidation afforded (R)-aldehyde 12, 9 which was transformed in secondary alcohol 13, 10 by treatment with 1-bromopentyl magnesium. Then, oxidation of 13 with PCC afforded 5-ketone 14, and deprotection of the silylether with tetrabutylammonium fluoride (TBAF) in tetrahydrofuran gave compound 9 11 in 26% overall yield from lactone 6 (Scheme 2).Since compound 9 is a synthon for the above mentioned glycosylation reactions, and it is prone to an intramolecular cyclization reaction to give a six-membered cyclic Downloaded by: Rutgers University. Copyrighted material. 1380 P. Ferraboschi et al. LETTER Synlett 2001, No. 9, 1379-1382 ISSN 0936-5214 © Thieme Stuttgart · New York hemiacetal, we protected the carbonyl function by synthesizing both (R)-ketal 15 12,13 and (R)-thioketal 16 14 (Scheme 2).As an illustration of the applicability of these novel g...

Synthesis of Isosteric Analogues of Acylglycosylglycerols Active as Chemoprevention Agents

“…Compounds 5a؊b were obtained as described in ref. [12] NaH was washed three times with hexane to remove the oil prior to use.…”

“…[12] As noted in the introduction, these synthons were planned as common acceptors for the construction both of the glucosyl-and of the galactosylglycerol analogues, through glycosylation reactions. They have the primary hydroxy group protected as a benzyl ether and the secondary hydroxy group free for conjugation with a suitable sugar.…”

“…A solution of 1-triphenylphosphoranylidene-2-heptanone (0.67 g, 1.8 mmol) (prepared according to ref. [12] and purified by flash chromatography: EtOAc/iPrOH, 8:2) in dry THF (5 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with water (20 mL), and extracted with dichloromethane (3 ϫ 40 mL). The combined organic extracts were washed with water and brine, and dried with sodium sulfate, and the solvents were evaporated under reduce pressure.…”

“…A retrosynthetic analysis of the isosteric structures showed that two different approaches should be suitable for efficient synthesis of the desired derivatives; on the one hand the analogues at the sugar moiety 1b؊d should be easily accessible from alcohol 4 by alkylation, or by oxidation to aldehyde followed by Wittig olefination, while on the other hand, for the analogues at the glycerol moiety, it should be more convenient to synthesize the glycerol analogues 5a؊c first and then to couple them with the appropriate sugar derivative (Figure 2). In a very recent paper [12] we reported the synthesis of the glycerol isosters 5a؊c and, as examples of their potential as carbohydrate acceptors, the synthesis of the glycoglycerolipid analogues 2d and 3d.…”