Sugars branched chain

More than a dozen branched-chain, deoxy sugars have now been discovered as components of antibiotics. One review on their biosynthesis4 and two5,6 on the chemistry and biochemistry of branched-chain sugars have appeared. These sugars can be divided into two groups according to their biosynthesis. 

Group 1 includes methyl-branched sugars and sugars having a two-carbon branch. These sugars arise by transfer of a Cj or C2 unit from appropriate donors to nucleotide-bound hexosuloses. 

Group 2 consists of sugars having a hydroxymethyl or formyl branch. These sugars are formed by intramolecular rearrangement of nucleotide-bound hexosuloses, with ring contraction and expulsion of one carbon atom. 

Besides the methylation step, the following reactions are necessary for the synthesis of dTDP-L-mycarose from dTDP-D-glucose reduction at C-2, inversion of configuration at C-5, and (possibly as the last 

SCHEME 1.—Postulated Reaction-sequence for the Biosynthesis of dTDP-L-mycarose (6) from dTDP-D-glucose. 

Provisional recommendations for naming branched-chain sugars have been published. A review on the chemistry and biochemistry of brcinched-chain sugars has appeared (in Japanese).  

6-Deoxy-3-C-methyl-L-gulose has been identified as the carbohydrate constituent of the antibiotics chrysomycin A and B, linked as a 6-pyranose C-glycoside.  

The 4-ulose (7) derived from glucose reacts stereospecifically with methyl lithium at -78° to give the 4-C-methyl glucose adduct which was used to prepare the moenuronic acid glycoside (8) at the same temperature, methyl magnesium iodide gave the D-galacto-isomer specifically.  

5-anhydro-hexen-3-ulose (15) obtained from triacetyl glucal gave an equimolar mixture of ribo- and arabino-3-C-methyl branched-chain derivatives (16) on treatment with methyl lithium. 

A synthesis of L-streptose from L-arabinose has been described 

Details of the synthesis of a derivative of pillarose (2,3,6-trideoxy-4-C-gIycolyl-L-threo-hexose) by Paulsen s group have been published (see Vol 10, p. 98). 

Partial hydrolysis of the meso-oxyphosphorane obtained when butanedione reacts with the 1,3,2-dioxaphospholene (364) gave two cyclic phosphotriesters [e.g. (365)] that differ in the configuration at the phosphorus atom. Further 

The cyanohydrin (368 R = CN) has been prepared in high yield by reaction of l,2 5,6-di-0-cyclohexylidene-a-D-n7 o-hexofuranos-3-ulose with potassium hexa-cyanoferrate(iii) and potassium carbonate. Mild hydrolysis of (368 R = CN) gave the 3-C-carboxamide (368 R = CONH2). 

The value of the 1,3-dithian route to branched-chain sugar derivatives has been illustrated further by stereospecific syntheses of 3-C-formyl, 3-C-hydroxymethyl, and 3-C-methyl derivatives of D-psicose from the ketone (373) via the dithianyl adduct (374). Addition of nitromethane to (373) gave both 3-C-nitromethyl-o-psicose and -fructose derivatives, which, after separation by chromatography, were reduced to the corresponding 3-C-aminomethyl derivatives. The use of dithianyl derivatives in the synthesis of streptomycin components is dealt with in Chapter 18. 

Treatment of methyl 3-0-benzoyl-4,6-0-benzylidene-a-D-arohmo-hexopyrano-sid-2-ulose with an excess of methyl magnesium iodide gave, as the main product, methyl 4,6-0-benzylidene-2-C-methyl-ot-D-glucopyranoside.  

The chemistry and biochemistry of apiose have been reviewed.  

A -Ray analysis of the antibiotic pillaromycin A has shown that the constituent branched-chain sugar (pillarose) has the structure (246), although it was 

Reagents i, CHj=CHMgBr ii, OsO -HgOj-Bu OH iii, PhsP=CHCO,Me iv, LiAlH -Et,0 V, TrCl-py vi, OsO -py vii, DMSO-DCC-H+ viii, HCl-CHCl, 

The details of two closely related syntheses of vinelose (6-deoxy-3-C,2-0-di-methyl-L-talose) and of a synthesis of methyl D-aldgaroside (methyl 4,6-di-deoxy-3-C-[(5 )-l-hydroxyethyl]-/S-D ri6o-hexopyranoside 3,3 -cyclic carbonate) have appeared (see Vol. 8, p. 103). 

It has been established that the kinetically favoured product formed on the addition of cyanide ion to l,2 5,6-di-0-isopropylidene-a-D-r/6o-hexofuranos-3-ulose has the D-a//o-configuration, whereas the thermodynamically favoured product has the D- / co-configuration. Conversion of the D-a/to-isomer into the lactone derivative (248) was used to establish its stereochemistry. Other branched-chain derivatives, including the amino-sugar (249), were also prepared. 

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Branched-chain sugars are found in nature, eg, cladinose, ie, 2,6-dideoxy-3-C-meth5l-3-0-methyl-L- 7 (9hexose [3758-45-0] a component of erythromycin. 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

Structure and Reactivity of Anhydro-sugars. Part I. Branched-chain Sugars. Part I. Action of Di-ethylmagnesium on Methyl 2 3-Anhydro-4 6-0-benzylidene-a-D-mannoside, A. B. Foster, W. G. Overend, M. Stacey, and G. Vaughan,/. Chem. Soc., (1953) 3308-3313. 

Triple bonds and cumulative double bonds 2-Carb-18. Branched-chain sugars... 

Two branched-chain sugars, methyl 3-azido-4,6-0-benzylidene-2,3,-dideoxy-3-C-(fluoromethyl)-a-D-flraZ)/ o-hexopyranoside and methyl 2-azido-4,6-0-benzylidene-2,3-dideoxy-2-C-(fluoromethyl)-) -D-r/to-hexo-pyranoside have been prepared through the usual displacement reactions. 

The branched-chain sugar fluoromethylphosphonate (573) was pre-pared by treatment of l,2 5,6-di-(7-isopropylidene-a-D-r/7)0-hexofur-anos-3-ulose (572) with lithio(fluoromethyl)diisopropylphosphonate (0x0-lane, — 78° room temp.) to give a diastereoisomeric mixture having the vt-allo configuration. 

Before 1983, branched-chain sugars had not been found in bacterial polysaccharides, but there are now five examples belonging to this class. The LPS from Coxiella burned phase I contains both 6-deoxy-3-C-methyl-L-gulose (L-virenose) as pyranoside (12) and 3-C-(hydroxymethyl)-L-lyxose as furan-oside (13). Another 6-deoxy-3-C-methylhexose, having the manno configuration, is a component of the Nitrobacter hamburgiensis 0-antigen. ... 

The aqueous Heck coupling reaction was also used for the synthesis of unprotected branched-chain sugar. In the media of DMF-H2O (5 1) and the use of Pd(dba)2 and P(o-tol)3 the Heck reaction proceeded smoothly to give the coupling product with high yield (up to 84%) (Eq. 3.38).148... 

In addition to the foregoing examples, periodate oxidation has been applied to isotopically labeled sugars (for the determination of label distribution), 226 -226 to certain branched-chain sugars,227-229 and to some nitrogenous derivatives of the simple sugars.230-236... 

It has been suggested15 that apiose [3-(hydroxymethyl)-D-g cero-tetrose] (LVII), a branched-chain pentose,47 originates from the aldol reaction of dihydroxyacetone with glycolaldehyde. The origin of this and all other branched-chain sugars so far encountered in natural products is uncertain, but they may arise from intermediate branched-chain carboxylic acids which are believed to be formed in the fixation of carbon dioxide (see above). 

The general chemistry of branched-chain sugars has not been the subject of systematic investigation, mainly because of the scarcity of these compounds. Nevertheless, the totality of reactions employed for elucidating the unique structures of these compounds constitutes a body of valuable information which is basic for future developments. Lucid articles on the chemistry of streptose, by Lemieux and Wolfrom,1 and of apiose, by Hudson, have appeared in earlier volumes of this Series the present article will therefore not include information on these two sugars, except as regards comparison with other sugars and in reference to new developments. 

The carbohydrate nomenclature jointly established by the American and British Committees4 does not specifically refer to the branched-chain sugars nevertheless, the application and extension of its Rules can provide definitive names to augment or to replace the trivial or unsystematic terms which have been conferred on naturally occurring, branched-chain sugars and related synthetic products, including the branched-chain saccharinic acids.6 9... 

A systematic nomenclature, besides correlating the above products, can remove the difficulties which have, in certain cases, been encountered on employing the trivial name of a branched-chain sugar in naming its derivatives. 7 9... 

Streptose is the first branched-chain sugar to have been identified as a component of a biological compound produced by a microorganism. This dicarbonyl sugar is known only in its derivatives. The chemistry of streptose and streptomycin has been lucidly reviewed by Lemieux and Wolfrom.1 In this article, it was noted that streptose must be either 5-deoxy-3-C -formyl-L-ribose or 5-deoxy-3-C-formyl-L-lyxose. Since then, the presence of the latter configuration (XXXIV) has been definitely established by Wolfrom and DeWalt,66 who found that N-acetyltetrahydrostreptobi-... 

The favored oxidative cleavage of a primary-secondary over a primary-tertiary vicinal diol grouping has been utilized in the synthesis of branched-chain sugar derivatives.482,483... 

Finally, when L-sorbose (81) was treated with hydrogen cyanide, a branched-chain, sugar lactone was formed which was characterized by converting it into a diacetal.127 An X-ray structure determination of this material revealed it to be 2,21 5,6-di-0-isopropylidene-[2-C-(hy-droxymethyl)-L-gulono-l,4-lactone] (82). However, all subsequent efforts to prepare 82 resulted in the formation of 2,3 5,6-di-0-isopropyli-dene-2-C-(hydroxymethyl)-L-gulono-l,4-lactone (83). 

Diisobutylaluminum hydride was also employed (153) for the reduction of 2,6-dideoxy-3-C-methyl-D-arabmo-hexono-1,4-lactone (121) to an antibiotic component, the branched-chain sugar evermicose (2,6-dideoxy-3-C-methyl-D-nrabmo-hexose, 122). The L-enantiomer of 122 (olivomycose, 125a), L-amicetose 125b, and 2,6-dideoxy-3-C-methyl-L-n Zw-hexose (l-... 

Unsaturated branched-chain sugars were synthetized with 72-84 % yield from both protected and unprotected 2-bromo-D-glucal with methyl acrylate in CH3CN/H2O 5/1 or in DMF/H2O 5/1 with a catalyst prepared from [Pd(DBA)2] and P(o-tolyl)3. Et3N or K2CO3 + /1-BU4NHSO4 could be used as base with similar results. 

A simple synthesis of the branched chain sugar, 2-C-methyl-D,L-lyxofuranoside 17 has been achieved by using the tin(ll) enolate of a I 3-dihydroxy-2-propanone derivative and methyl pyruvate (23). 

As was described for phthalan 330, the intermediate 374 has also been nsed for the EPC synthesis of branched-chain sugars 378 and 379"° and the steroid 380 in 15-70% yield, employing ketones 133 and 270, as well as 280, respectively. 

K. Sato and J. Yoshimura, Branched-chain sugars. XII. The stereoselectivities in the reaction of methyl 4,6-O-benzylidene-a- and -p-D-hexopyranosid-3-uloses with diazomethane, Bull. Chem. Soc. Jpn., 51 (1978) 2116-2121. 

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