Deoxy Sugars

4 Syntheses of 6-Deoxy-2 and 3-O-Methyl-Dallose and Some 6-Deoxyhexopyranoside Phenylboronates J. S. B R I M A C O M B E , A. H U S A I N , F. H U N E D Y , and M. STACEY

Downloaded by UNIV LAVAL on May 5, 2016 | http://pubs.acs.org Publication Date: June 1, 1968 | doi: 10.1021/ba-1968-0074.ch004

The University of Birmingham, Birmingham, England.

New reagents that are of value in the oxidation of partially protected sugars are reviewed briefly. 6-Deoxy-3-O-methylD-allose, a component sugar of the sarcostin glycosides of Ascelepias lilacina Weimarck and A . swynnertonii S. Moore, has been synthesized by way of methyl 4,6-O -benzylidene-2-O-toluene-p-sulfonyl-α-D-ribo-hexopyranosid3-ulose. The same compound has also been used in two syntheses of javose (6-deoxy-2-O-methyl-D-allose), a constituent of two cardenolides found in the seeds of Antiaris toxicaria Lesch. Condensation of methyl 6-deoxy-ß-D-allo -and gluco-pyranoside with triphenylboroxole afforded a cyclic 2,4-phenylboronate, in each case. In an analogous reaction with methyl α-L-rhamnopyranoside and methyl α-L-fucopyranoside, 2,3- and 3,4-cyclic esters, respectively, were formed. Preliminary results of the oxidation of some glycoside phenylboronates with methyl sulfoxide and acetic anhydride are reported.

The replacement of a secondary hydroxyl group by a carbonyl group in pyranoid and furanoid rings provides a versatile functionality for further synthesis (9, 45). Details of the preparation and chemistry of carbohydrates containing a carbonyl group, i n addition to that at C ( l ) , have appeared (31, 53) relatively recently but several important developments have since taken place i n this area. These stem from the introduction of new oxidation procedures—e.g., ruthenium textroxide (6, 7), acid anhydride-methyl sulfoxide (1,2), dicyclohexylcarbodiimide-methyl sulfoxide-pyridinium phosphate (47)—which promise to make ketosugars more readily available for synthetic work. The scope of these new 56

Hanessian; Deoxy Sugars Advances in Chemistry; American Chemical Society: Washington, DC, 1968.


4.

BRIMACOMBE E T A L .

6-Deoxy-2 and 3'O-Methyl-D-allose

57

oxidation reagents w i l l be reviewed briefly, together with their application to the synthesis of two naturally-occurring methyl ethers of 6-deoxyD-allose. I n addition, preliminary investigations on the oxidation of some carbohydrate phenylboronates, with acetic anhydride-methyl sulfoxide (1), w i l l be described. In 1964, Beynon, Collins, and Overend (6) reported that ruthenium tetroxide is an extremely potent oxidant for preparing the partially protected glycopyranosiduloses. This reagent offered distinct advantages over the chromium trioxide-pyridine complex, the reagent usually employed (45, 53), and affected neither glycosidic, ester, acetal, nor ketal substituents i n the oxidized molecule ( 6 ) . Oxidation is achieved either at room temperature with a slight excess of ruthenium tetroxide (prepared from the dioxide with sodium metaperiodate) i n carbon tetrachloride, or, less satisfactorily, with a catalytic quantity of the tetroxide in the presence of sodium metaperiodate. T h e latter procedure, however, was developed by Parikh and Jones (46) into a single-stage oxidation which gave essentially quantitative yields of oxidized products. In passing, this reagent fulfills the long-standing need (5) for an oxidant which functions under neutral conditions at ambient temperature. Of particular value, was the reagent's ability to oxidize a hydroxyl group attached directly to a furanoid ring (6, 7, 46), as is illustrated by the conversion of l,2:5,6-di-0-isopropylidene-a-D-glucofuranose into l,2:5,6-di-0-isopropylidene-a-D-rf6o-hexofuranos-3-ulose ( 1 ) . The follow-

1 ing keto-sugars are among those which have been prepared, i n good to quantitative yield, using the ruthenium textroxide procedures (6, 7, 4 6 ) : methyl 6-deoxy-2,3-0-isopropylidene-«-L-/t/xo-hexopyranosid-4-ulose, 6deoxy-1,3:2,5-di-0-methylene-L-fyxo-hex-4-ulose, methyl 3,4-O-isopropylidene-j#-L-ert/£/iro-pentopyranosidulose, methyl 4,6-0-benzylidene-2-deoxya-n-erythro and f/ireo-hexopyranosid-3-ulose, methyl 3,4,6-tri-O-benzoyla-D-amfcino-hexopyranosidulose, 6-0-benzoyl-l,2:4,5-di-0-isopropylideneD-*(/Zo-hex-3-ulose, and methyl 6-deoxy-3,4-0-isopropylidene-a-L-Zt/xohexopyranosidulose. Another significant development i n the oxidation


58

DEOXY SUGARS

of partially protected carbohydrates arose through the introduction of methyl sulfoxide-carbodiimide-pyridinium phosphate (47) and related oxidants (1, 2). The former combination of reagents was discovered by Pfitzner and Moffatt (47, 48) when attempting to polymerize thymidine 5~-phosphate using dicyclohexylcarbodiimide i n anhydrous methyl sulfoxide. W i t h these reagents, the nucleotide was degraded completely to thymine and a second product (2) was also formed if an excess of pyridine was added. It was shown (48) subsequently that only nucleotides containing an unsubstituted 3'-hydroxyl group underwent rapid and complete cleavage of the N-glycosidic and ester bonds. Degradation was attributed to oxidation of the 3'-hydroxyl group to a ketone OH


OH

| e

cr

CH SMe

ROCH

2

AcO

(3), which underwent spontaneous ^-elimination of the base and phosphate group. This argument is enhanced by the recent isolation (19) of 2'- and 3'- ketouridine following similar oxidation and detritylation of 3',5'- and 2',5'-di-0-trityluridine, respectively. It is also pertinent to record that oxidation of 3'-0-acetylthymidine yielded the aldehydo-compound (4) without concomitant formation of carboxylic acid derivatives. The facile and selective oxidation of both primary and secondary hydroxy groups with certain nucleotides led Pfitzner and Moffatt (48) to explore the scope of the carbodiimide-methyl sulfoxide reagent with steroid and alkaloid alcohols. Relatively minor differences were apparent in the rate of oxidation of epimeric pairs of 3- and 17- hydroxy steroids whereas the equatorial l l a - h y d r o x y l group i n several steroids was readily oxidized under conditions where the axial epimer was unreactive [cf. chromic oxide oxidation (51)]. The mechanism of the oxidation reaction, resulting from treatment of an alcohol with dicyclohexylcarbodiimide and methyl sulfoxide in the presence of a proton source, was elucidated by isotope experiments (24). These confirmed that the reaction proceeded by formation of a


4.


59

6-Deoxy-2 and 3-O-Methyl-Thailose

sulfoxide-carbodiimide adduct (5) which was attacked by the alcohol to give an alkoxysulfonium salt (6). This undergoes abstraction of a proton from the a-carbon atom and concerted collapse of the resulting intermediate 7 with formation of the carbonyl compound and methyl sulfide. The intermediacy of alkoxysulfonium salts relates this reaction to the oxidation of various reactive alkyl halides, alkyl sulfonates, and a-halogeno esters on heating with methyl sulfoxide in the presence of a proton source (3, 34, 37, 38, 39, 43). Oxysulfonium salts are also intermediates i n the reactions of methyl sulfoxide with alkyl chloroformates (5) and with alcohols i n the presence of acid anhydrides (see below). C e H n N ^ C ^ N C e H u + Me SO Downloaded by UNIV LAVAL on May 5, 2016 | http://pubs.acs.org Publication Date: June 1, 1968 | doi: 10.1021/ba-1968-0074.ch004

2

R C = 0 + Me S 2

6

2

7

Following closely on the foregoing oxidation procedure, Albright and Goldman (1,2) described a novel method for the oxidation of alcohols which uses methyl sulfoxide and certain acid anhydrides—e.g., acetic



60

DEOXY SUGARS

anhydride, benzoic anhydride, or phosphorus pentoxide. The method appears to be generally applicable and is claimed to be of particular value for the oxidation of sterically hindered hydroxyl groups. The mechanism of the oxidation of alcohols with methyl sulfoxide and acid anhydrides has been discussed recently by Albright and Goldman (2). Although acyloxysulfonium salts are undoubtedly intermediates i n the oxidation (c.f., Reference 49) the way in which these break down to give the carbonyl compound and methyl sulfide is by no means established. A review of oxidations using methyl sulfoxide is now available (23). These new oxidation procedures were quickly applied in the carbohydrate field w i t h remarkable success. Oxidation of 5-deoxy-l,2-0isopropylidene-/?-L-arabinofuranose with the Pfitzner-Moffatt reagent (48) gave the keto-sugar 8, which was ultimately transformed into L streptose (5-deoxy-3-C-formyl-L-lyxose) (22), thus providing the first constitutional synthesis of this elusive antibiotic sugar. A more extensive appraisal of the Pfitzner-Moffatt reagent was conducted by Baker and Buss (4) who prepared the keto-sugars 9 and 10, in high yield, from / O—CH ! ^ O—C—H 2

Me,C

PhCH MsO—C—H

.K

, 'OMe

C=0 | H—C—CK ! H C—

OTs CMe

2

2

8

9

10

l,2:5,6-di-0-isopropylidene-3-0-methanesulfonyl-D-mannitol and methyl 4,6-0-benzylidene-2-0-toluene - p - sulfonyl -a-D- glucopyranoside, respectively. In some instances, oxidation of a carbohydrate secondary hydroxyl group—e.g., in 1,2:5,6-di- O-isopropylidene-a-D-glucofuranose— was not achieved, and it would appear that the reagent has certain limitations. Fortunately, the oxidation of l,2:5,6-di-0-isopropylidene-«-D-glucofuranose to l,2:5,6-di-0-isopropylidene-a-D-nbo-hexofuranos-3-ulose (1) can be accomplished using either phosphorus pentoxide (10, 44) or acetic anhydride (10, 52) i n methyl sulfoxide; although this oxidation is effected with ruthenium tetroxide (6, 7, 46), it is exceeding difficult with other oxidizing agents (53). Keto-sugar 1 is reduced stereospecifically


4.


6-Deoxy-2 and 3-O-Methyl-D-aIlose

61


(54) with sodium borohydride to l,2:5,6-di-0-isopropylidene-a-D-allofuranose and so provides a convenient and cheap route to D-allose. Oxidation of l,6-anhydro-2,3-0-isopropylidene-/?-D-mannopyranoside and 2,3:5,6-di-O-isopropylidene-a-D-mannofuranose with methyl sulfoxideacetic anhydride gave high yields of l,6-anhydro-2,3-0-isopropylidene-/?D-Zt/xo-hexopyranos-4-ulose and 2,3:5,6-di-O-isopropylidene-D-mannono1,4-lactone (33), respectively. The use of methyl sulfoxide-acetic anhydride offers advantages i n that the oxidized product can be isolated simply by lyophilization of the excess of reagents and crystallization. Rearrangement of methyl 4,6-0-benzylidene-3-deoxy-3-phenylazoaldohexopyranosides with alkali provides a new route to hexosid-3uloses (18). As part of a program i n this laboratory on the reactions of D-allose derivatives, we have been concerned with the synthesis of some naturallyoccurring methyl ethers of 6-deoxy-D-allose. Mycinose [6-deoxy-2,3-di-0methyl-D-allose (21)] is a constituent of the macrolide antibiotic chalcomycin and its synthesis has been reported (15,16) already. 6-Deoxy-3O-methyl-D-allose is now known to be a component of the sarcostin glycosides of Ascelepias lilacina Weimarck (50) and Ascelepias swynnertonii S. Moore (36). A facile entry into the D-allopyranoside series can be achieved by stereospecific reduction, with sodium borohydride, of methyl 4,6-0-benzylidene-2-0-toluene-p-sulfonyl-a-D-rffco-hexopyranosid3-ulose (10) to yield (4) methyl 4,6-0-benzylidene-2-0-toluene-psulfonyl-a-D-allopyranoside (11). Compound 11 was then converted (14) into 6-deoxy-3-0-methyl-D-allose (12) by a series of well-established reactions (Figure 1). Alternatively, this sugar has been prepared (40) by partial benzoylation of methyl 6-deoxy-/?-D-allopyranoside to give the 2,4-di-O-benzoate followed by methylation at C ( 3 ) and removal of the protecting groups. A n isomeric sugar, D-javose, is a constituent of two cardenolide glycosides (strophanthojavoside and antiarojavoside) found (42) in the seeds of Antiaris toxicaria Lesch. Degradative studies indicated (42) that javose had the structure 6-deoxy-2-0-methyl-D-allose (17) and this assignment was confirmed by two stereospecific syntheses. In the first approach (13) methyl 4,6-0-benzylidene-2-0-toluene-psulfonyl-a-D-allopyranoside (11) was transformed by successive benzylation and alkali treatment into methyl 3-0-benzyl-4,6-0-benzylidene-

Deoxy Sugars

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