Synthesis of 6-Deoxy-4-aminohexoses from Cyclopentanones

Abstract

Procedures for the conversion of (±)-2-methoxy-2-methyl-3-oxazolidinylcyclopentanone into a variety of 4-amino-6-deoxyhexoses have been developed. These involve Baeyer-Villiger ring expansions, reductive methylations and epimerizations.Keywords: (±)-2-methoxy-2-methyl-3-oxazolidinylcyclopentanone, 4-amino-6-deoxyhexoses, Baeyer-Villiger ring expansions, reductive methylation, epimerizations 6-Deoxyaminohexoses are common aminosugar fragments found in many antibiotic and antitumor agents, as well as in the cell walls of many bacteria. 6-Deoxy-3-aminohexoses are the most common of the aminosugars, and these have been the focus of substantial synthetic effort. 1 6-Deoxy-4-aminohexoses are considerably less common, and as a consequence, synthetic approaches to these have been less developed. Biologically active members of the latter class include: ossamine 1, the aminosugar fragment from the fungal metabolite ossamycin; 2 methyl-L-kedarosaminide 2, from the ene-diyne antitumor agent kedarcin; 3 callepeltose 3, from the antitumor cyclodepsipeptide callipeltose; 4 and the aminosugar moiety of antibiotic C-1027 4 ( Figure 1). 5 Synthetic precursors to these 6-deoxy-4-aminohexoses include compounds from the "chiral pool" such as threonine, 3c,d,6a ethyl lactate, 3e rhammose, 4,7 glucose, 2,3b and less commonly from precursors synthesized asymmetrically. 5,8 Recent research in these laboratories has been directed toward the utilization of chiral cyclobutanones, produced by the photochemical reaction between chromium carbene complexes and chiral ene carbamates, 9 as precursors to biologically active compounds via ring expansion procedures. These include 4-disubstituted butenolides, 10 4-disubstituted nucleoside analogs, 11 carbacyclic nucleoside analogs, 12 and aminocyclopentitols. 13 The development of synthetic approaches to 5-methoxy analogs of 4-amino-6-deoxyhexoses are described below.The key starting material for these studies, cyclopentanone 5, was available in two steps and 60-70% overall yield by the diazomethane ring expansion 14 of the photochemically generated 2-methoxy-2-methylcyclobutanone. Treatment with m-CPBA resulted in clean Baeyer-Villiger rearrangement 10a with exclusive migration of the more-hindered terminus with complete retention of configuration to produce lactone 6 in excellent yield (Scheme 1). This lactone was quite sensitive to acidcatalyzed epimerization at the anomeric (ketal) carbon and required removal of all traces of m-chlorobenzoic acid (aqueous NaHCO 3 ) followed by immediate purification by flash chromatography.Conventional DIBAL-H reduction of the lactone to the lactol resulted in ring opening because of the methoxide leaving group. However, quenching the low temperature DIBAL-H reduction with acetic anhydride in the presence of pyridine and DMAP 15 produced lactol acetate 7 in excellent yield as a 1:1 mixture of diastereoisomers at the acetate-bearing center. Treatment of this mixture with BF 3 etherate in methanol cleanly exchanged the acetate for a methoxy group giving 8 again as ...

Photoinduced Reactions of Metal Carbenes in Organic Synthesis

“…Palladium-catalyzed allylic amination with common nucleoside bases in the presence of chiral phosphines resulted in kinetic resolution to give a single b-epimer (Scheme 3) [77]. This same optically active cyclobutanone intermediate was the starting point for the synthesis of (-)-cyclobut-A, (±)-3¢-epi-cyclobut-A [78], carbovir and aristeromycin [79], and (+)-neplanocin A [80], as well as aminocyclopentitols [81] and, from the (methoxy)(methyl) analog, 6-deoxy-4-aminohexoses (Scheme 4) [82].…”

Effect of Adjacent Chiral Tertiary and Quaternary Centers on the Metal-Catalyzed Allylic Substitution Reaction

“…α-Selenation followed by oxidation and spontaneous elimination gave cyclopentenone 3 in 64% yield. Reduction with Luche conditions provided a 4.5:1 mixture of epimeric allylic alcohols 16b …”

“…Materials. The following compounds were prepared according to literature procedures: cyclobutanone 2 ,16a diazomethane, (±)-2-benzenesulfonyl-3-phenyloxaziridine (Davis' oxaziridine), [η 3 -C 3 H 5 PdCl] 2 , Pd(PPh 3 ) 4 , N[(CH 2 ) 3 ] 3 SnCl ( 11 ),28b N[(CH 2 ) 3 ] 3 SnMe ( 12c ),27b phenyllithium, and vinyllithium…”

“…Research in these laboratories has recently focused on the utilization of chiral cyclopentanones, derived from the ring expansion of photochemically produced cyclobutanones, as intermediates in natural product synthesis . Cyclopentanone 1 14 could also be easily converted into substrates for the metal-catalyzed allylic substitution reaction, which would allow for the study of the effect of highly substituted β-positions (eq 1).…”

Photoinduced Reactions of Metal Carbenes in Organic Synthesis

“…Palladium-catalyzed allylic amination with common nucleoside bases in the presence of chiral phosphines resulted in kinetic resolution to give a single b-epimer (Scheme 3) [77]. This same optically active cyclobutanone intermediate was the starting point for the synthesis of (-)-cyclobut-A, (±)-3¢-epi-cyclobut-A [78], carbovir and aristeromycin [79], and (+)-neplanocin A [80], as well as aminocyclopentitols [81] and, from the (methoxy)(methyl) analog, 6-deoxy-4-aminohexoses (Scheme 4) [82]. …”