Unusual sugars of the GPL-type antigen of Mycobacterium avium serovar 19. Stereoselective synthesis of methyl 6-deoxy-3-C-methyl-2,4-di-O-methyl-α-L-mannopyranoside and its C-4 epimer

Abstract

Completely reversed stereoselectivity of reduction of methyl 6-deoxy-2,3-O-isopropylidene-3-C-methyl-α-L-mannopyranoside (2) and its deisopropylidenated derivative (7) was observed. Compound 2 gave exclusively the L-talo-isomer (3) with NaBH 4 in MeOH, but the reduction of 7 with NaBH 4 in acetic acid resulted in the L-mannoderivative 8. It is assumed that in the first case the stereoselectivity is determined by the steric accessibility of the carbonyl group, while in the second case free OH-groups direct the selectivity of the reduction by complexation or ligand exchange.Members of the Mycobacterium avium serocomplex 1,2 are opportunistic pathogens and can cause serious infections. Structural analysis of the cell-surface glycopeptidolipid-type (GPL) antigen of serovar 19 showed that it contains the O-linked pentasaccharide 1 3 . While most of the structural features of the penultimate residue ( Fig.) have been determined, ambiguity persists regarding the stereochemistry at C-4 of this unit.Here we report stereoselective syntheses of both epimers (6, 12) of the unidentified unit as their methyl glycosides in the proposed, α anomeric forms 3 . Precursor to both targets was methyl 6-deoxy-2,3-Oisopropylidene-3-C-methyl-α-L-lyxo-hexopyranosid-4-ulose (2) that was prepared as described by Klemer from L-rhamnose in four steps 4 . Reduction of compound 2 either with NaBH 4 or with LiAlH 4 (Scheme) resulted in the 6-deoxy-L-talo isomer 3 exclusively, as confirmed by the low value (1 Hz) of the 3 J 4,5 coupling constant. The complete stereoselectivity of this reduction can be explained by the extremely crowded β-(L) side of compound 2: the hydride anion can approach the C-4 carbon atom only from the α-(L) face. Methylation of compound 3 resulted in 4 from which the isopropylidene group was removed by acidic hydrolysis to obtain 5. Methylation of the axial OH-2 of 5 required rather drastic conditions to give 6, and formation of the fully methylated product (13) was also observed (15 %). Compound 13 exists exclusively in 4 C 1 (L) conformation. SchemeFigure Downloaded by: York University libraries. Copyrighted material. LETTERS SYNLETTTo prepare the rhamno-isomer (12) from compound 2, its isopropylidene group was hydrolyzed, then the free ulose-derivative (7) was treated with NaBH(OAc) 3 (Scheme 1) 5,6 . Methyl α-Levalopyranoside was isolated in nearly quantitative yield. In its 1 H-NMR spectrum H-4 gave a doublet at 3.39 ppm having 3 J 4,5 10 Hz, that confirms the trans-diaxial relationship of the H-4 and H-5 protons. The completely reversed stereoselectivity compared to the reduction of 2 could only be achieved in the presence of the free OH groups suggesting that these play a role in the complexation of the hydride donor thus governing the direction of the attack of the hydride anion. Isopropylidenation of 8 gave compound 9 and after methylation (→10) and deprotection (→11) the resulting diol was selectively methylated at OH-2 at 0 °C under phase-transfer conditions. The isolated yield of compound 12 was 67 % after chro...

Phorbasides A−E, Cytotoxic Chlorocyclopropane Macrolide Glycosides from the Marine Sponge Phorbas sp. CD Determination of C-Methyl Sugar Configurations

“…Attempted reduction of ketone 13 under a variety of kinetic and thermodynamic conditions (Table ) produced only 15 or poor conversion to 14 (entries 6 and 7, <8%). Successful conversion of 13 to the desired diastereomer 14 was achieved by using a variant of Lipták’s procedure that allowed hydride reduction to proceed under the direction of the C3 hydroxyl . Removal of the acetonide in 13 (acetone, PPTS, reflux) gave keto-diol 16 , which was reduced (NaBH(OAc) 3 , AcOH) to alcohol 17 exclusively .…”

“…Successful conversion of 13 to the desired diastereomer 14 was achieved by using a variant of Lipták’s procedure that allowed hydride reduction to proceed under the direction of the C3 hydroxyl . Removal of the acetonide in 13 (acetone, PPTS, reflux) gave keto-diol 16 , which was reduced (NaBH(OAc) 3 , AcOH) to alcohol 17 exclusively . Reprotection of 17 as a C2/C3 acetonide (acetone, CuSO 4 , reflux) gave 14 (Scheme ), which was treated with 2-naphthoyl chloride (pyridine, CH 2 Cl 2 ) to provide the 4- O -naphthoate ester 18 in 82% yield.…”

Synthesis of the methyl ethers of methyl 6-deoxy-3-C-methyl-α-L-talopyranoside and -α-L-mannopyranoside. Examination of the conformation and chromatographic properties of the compounds

“…The sugar 17 was obtained by the acid hydrolysis of methyl 6-deoxy-2,3-O-isopropylidene-3-C-methyl-α-L-talopyranoside 5 (1). The sugar 36 was isolated earlier from a natural source, and following isolation and structural determination it was named nogalose 8,10 .…”

“…In order to synthesize the pentasaccharide, we prepared methyl 6-deoxy-3-C-methyl-4-Omethyl-α-L-manno-(22) and -talopyranoside (4), as well as methyl 6-deoxy-3-C-methyl-2,4-di-O-methyl-α-L-manno-(23) and -talopyranoside (5) 5 . In this way it was convincingly established that the sugar next to the last in the pentasaccharide has a mannose-configuration.…”

“…The required selective alkylations of the talopyranosides was achieved by sodium hydride-mediated reactions, whereas in the case of the mannopyranosides phase transfer-type catalysts were found most suitable. Methyl 6-deoxy-2,3-O-isopropylidene-3-C-methyl-α-L-talopyranoside (1) 5 , and -α-Lmannopyranoside (19) 5 were methylated by means of the Brimacombe method 6 to obtain the …”