Lincosamine derivatives

T. Atsumi, T. Fukuinara, T. Ogawa, and M. Matsui, A stereoselective synthesis of /V-acetyl-lincosamine derivatives, Agric. Biol. Chem. 37 2621 (1973). 

In the syntheses reported by Woolard and co-workers [26], the previously described nitro-compound 18 served as a starting material (Scheme 9). Epoxida-tion of 18, with alkaline hydrogen peroxide, resulted in a 5 1 mixture of isomers 44 and 45. Chromatographically pure epoxide 44 was then reacted with benzylamine to give the aminoketone 46 as the single product. Reduction of 46 with sodium borohydride afforded alcohol 47 and its 7-epimer 48 in a 12 1 ratio. Debenzylation of 47, followed by iV-acetylation, gave the previously described lincosamine derivative 15. 

Chromatographically pure compound 49 was reduced with sodium borohydride in propanol-2 to give, after N-acetylation, the lincosamine derivative 15 accompanied by its 7-epimer 21 in a 1.8 1 ratio. 

Scheme 12 presents a Hoppe and Schollkopf approach to the synthesis of azidoketone 49, a key-intermediate for preparation of the lincosamine derivative 15. 

A very interesting approach to the synthesis of 6-epi-lincosamine derivative 59 was presented by Bose and co-workers [29]. Using a Schiff base 31, derived from a chiral aldehyde 10, as the imine component in the Bose synthesis of -lactams (Scheme 13), resulted in an optically pure cis-product 57 as a single isomer. 

Hydrolytic cleavage of the -lactam bond gave compound 58. Conversion of the carboxy function to the methyl group afforded 6-epi-lincosamine derivative 59. 

While there are some problems with alcohol 72a, adduct 72b can be easily transformed into ulose 75, and then into the lincosamine derivative 79 (Scheme 18). This work is currently under investigation. 

Further transformation of adducts of type 100 involved oxidative shift of the double bond [56, 57], followed by cis-hydroxylation, to afford the lincosamine derivative 111 (Scheme 26). 

Similarly, 1,4-addition of azide to L-e yt/iro-hex-2-enopyranose provided a stereoselective route to the methyl and benzyl glycosides of L-acosamine (3-amino-2,3,6-trideoxy-L-am6ino-hexose). Inversion at C-4 yielded the L-daunosamine analogues, in the same manner as detailed above (ref. 23). Sugar aldehydes have been chain extended to unsaturated N-methylthiazolium salts such as (39) and (41), which were converted through Michael addition of benzylamine, to the 3-amino-2,3-dideoxy-0(-D-t/irco-pentopyranoside (40) and the 7-deoxy-6-e/7i-lincosamine derivative (42) as shown in Schemes 8 and 9, respectively. 3-epi-... 

The lincosamine derivative (107) has been prepared from the unsaturated nitro-sugar (106) by the sequence of reactions shown in Scheme 25. The... 

As well as yielding a mixture of epimeric ketoacetates, in which the epimer required for the synthesis of lincosamine derivatives is a minor component, acetolysis of the diazoketone also gave the 3-oxetanone (112) (19% yield), a product of pyranose-ring opening. 

The configuration of a keto-ether (301 R = OMe) obtained in 28% yield on methanolysis of the diazoketone (301 R = Nj) has been shown to have the i -glycero-ii-galacto configuration, rather than the d- or. -glycero- j-altro configuration previously suggested by c.d. (see Vol. 8, p. 135), by formation of the AT-acetyl-lincosamine derivative (302) and its C-6 epimer. ... 

Phase 3. Formation activation and modification of a putative NDP-heptose. We suggest that the heptose moiety is derived from erfo-heptulose-7-phos-phate, which is the universal source for heptoses in all organisms having a functional pentosephosphate cycle. Also, for C-7 cyclitols (e.g., valien-amine) or for secondary metabolic sugar units with longer C chains, such as octoses (e.g., lincosamine, or the octose unit in APR, see Section 2.2.4.2), this seems to be the preferred precursor in actinomycete pathways. ... 

The Synthesis of N-Acetyl-lincosamine (6-Acetamido-6,8-dideoxy-D-ert/fhro-D-ga-lacto-octose), a Derivative of the Free Carbohydrate Moiety in Lincomycin, G. B. Howarth, W. A. Szarek, and J. K. N. Jones, Chem. Commun., (1969) 1339-1340. 

In the course of their application to the natural product, Danishefsky provided a total synthesis of (+ )-lincosamine (Scheme 30) (83JA6715 85JA1274). An intermolecular hetero Diels-Alder reaction of the diene mixture 195 with crotonaldehyde (210) under the influence of trifluoroacetic acid at -78°C gave a 67% yield of the 2-[( )-l-propenyl]pyrone 211. Reduction of the ketone 211 by Luche s procedure (79JA5848) followed by benzoylation afforded the galactal derivative 212. Treatment of 212 with m-chloroperbenzoic acid in anhydrous methanol followed by benzoylation afforded the methyl galactoside 213. Reaction of 213 with N-bromosuccin-imide in the presence of wet acetic acid produced a single bromohydrin (214). 

As its methyl thioglycoside, lincosamine (6-amino-6,8-dideoxy-D- /7r/tro-D-ga/acto-octo-pyranose) is the saccharide portion of the clinically important antibiotic lincomycin. Racemic 3-methyl lincosaminide was prepared by Danishefsky and coworkers [140] who utilize the hetero Diels-Alder addition of crotonaldehyde to the Danishefsky s diene 268 to afford E) cA-2-(l-propenyl)-3-(benzyloxy)-2,3-dihydro-4-pyrone. The ZnBr2-catalyzed cycloaddition of 268 to A-carbobenzoxy-0-protected-D-a//(9-threoninal gives a 2 1 mixture of adducts 270 and 271 that has been converted into 272, a protected form of 6-amino-6,8-dideoxy-D- 77f/iro-L-ga/acto-octopyranose (Scheme 13.78). Analogously, the ZnBr2-promoted cycloaddition of the D-threoninal derivative 273 to 268 leads to a 3 1 mixture of adducts. The major adduct... 

An elegant total synthesis of the semiprotected form of lincosamine was realized by Marshall and Beaudoin [116]. An aldehyde derived from destomic acid (6-amino-6-deoxy-L-g/yc ro-D-ga/acto-heptonic acid) was derived in a similar way from a L-serinal derivative via hetero Diels-Alder addition to 1-ethoxy-3-[(trimethylsilyl)oxy]-4-benzyloxy-1,3-butadiene [142]. A similar method was applied to the preparation of a semiprotected form of anhydrogalantinic acid, a component of the antibiotic galantin I [142]. 

The presented review describes total syntheses directed towards 6-amino-6,8-dideoxy-D-eryt/iro-D-galacto-octose, commonly named lincosamine - the sugar component of the antibiotic lincomycin. In the first part we present total syntheses of lincosamine that start from carbohydrate precursors. The D-galactose-derived aldehyde is the most frequently used synthon. In the second part, total syntheses of lincosamine from non-carbohydrate precursors are presented. This part of the review is divided into two subsections. The first one groups syntheses based on the application of furan compounds. In the second one we present a hetero-Diels-Alder approach to the synthesis of lincosamine. 

Pfitzner-Moffatt oxidation of diisopropylidene derivative of D-galactose 12 gives aldehyde 10 [15] which served as a convenient synthon in several syntheses of lincosamine. 

Scheme 8 presents the David and Fisher approach to the synthesis of celestosamine [25], a very close derivative of lincosamine. The starting molecule is l,2 3,4-di-0-isopropylidene-a-D-galactopyranuronyl chloride 39 which in the reaction with diazoethane gives diazoketone 40 that is converted with methanol, in the presence of boron trifluoride, into a mixture of keto-ethers. 

Reaction of furyllithium (60) with L-threonine derived lithium salt 61 afforded the expected ketone 62 in 30% yield. Reduction of 62, using lithium aluminium hydride, gave two alcohols (63 and 64) in a 3 1 ratio. In both carbinols (63 and 64) the oxazoline ring was opened by acid hydrolysis to give the N-benzoyl derivatives 65 and 66, respectively. Alcohol 66 can be used in the synthesis of lincosamine enantiomer, but unfortunately this approach has limited preparative value because of the low yield obtained in the condensation step and, on the other hand, opposite diasteroselectivity obtained in the reduction reaction. 

The hetero-Diels-Alder reaction between 1-oxygenated or 1,3-dioxygenated buta-1,3-diene derivatives and carbonyl compounds is a convenient method for the preparation of sugars [38-41]. There are only few works connected with the application of this methodology to the lincosamine chemistry. 

Using a similar approach, compound 122 was transformed into the penta-acetyl derivative of lincosamine 132 (Fig. 2) [61]. 

Chiral P-lactams prepared from a 6-imino-D-galactose derivative have been used as synthons for 6-epz-lincosamine. ... 

The reactions of an epimino derivative of lincosamine with sulphides and the... 

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