Rapid access to rare natural pyranosides using 1,2-diacetal protected intermediates

摘要

J. Chem. Soc. Perkin Trans. 1 1997 2805 Rapid access to rare natural pyranosides using 1,2-diacetal protected intermediates Steven V. Ley,* Dafydd R. Owen and Kieron E. Wesson Department of Chemistry University of Cambridge Lensfield Road Cambridge UK CB2 1EW The synthesis of six rare methylpyranosides from common manno- and galacto-pyranoside starting materials has been achieved by the expedient use of 1,2-diacetal protecting group methodology highlighting its compatibility with a number of other common synthetic procedures. The use of 1,2-diacetals as protecting groups for trans-1,2-diols has been shown to be a particularly useful method for the effi- cient construction of complex biologically significant oligosaccharides. 1 Recently several parameters for the design and exploitation of these 1,2-dione reagents for the direct protection of trans-1,2-diols have been established.2 Although relatively few 1,2-diones are effective in these reactions they have proved to be a versatile and powerful new protecting group protocol.The high selectivity for trans-1,2-diols in the presence of other polyols rapidly leads to protected monosaccharides amenable for further synthetic manipulation. The additional tuning effect on the latent glycosidation reactivity of these 1,2-diacetal protected building blocks in oligosaccharide assembly further enhances their synthetic utility.3 In this work we describe the high yielding selective protection reaction of methyl-a-D-mannopyranoside and methyl-a- D-galactopyranoside with butane-2,3-dione affording the cor- Scheme 1 i cat. CSA CH(OME)3 MeOH heat; ii cat.BF3?OEt2 CH(OMe)3 MeOH room temp. O O O O O OMe OH OH OMe OMe O HO HO OH OMe OH O O O HO O OMe OMe OMe O OH HO HO O OMe HO OH + 2 3 1 i. or ii. + 1 i. 95 ii. 99 80 4 5 i. responding butane-2,3-diacetal (BDA) intermediates which may be further manipulated in the expedient synthesis of some rare monosaccharides using a range of standard synthetic procedures. These reactions take place with no degradation or loss of the 1,2-diacetal protecting group. Typically the BDA intermediates such as 3 and 5 may be prepared by the direct reaction of butane-2,3-dione 1 which is both cheap and commercially available with the parent monosaccharide in the presence of catalytic camphorsulfonic acid (CSA) and trimethyl orthoformate in boiling methanol (Scheme 1).2 The protection reaction may also be carried out at room temperature in high yield using boron trifluoridendash;diethyl ether as a Lewis acid (Scheme 1).The highly crystalline BDA products need little further purification. The protection of the trans-1,2-diol in monosaccharide 2 in the presence of a cis-1,2- diol pair and 1,3-related pair makes this high yielding selective process highly attractive. The single step BDA procedure also eliminates several steps from conventional approaches to this level of protecting group selectivity.4 These BDA protected intermediates were subjected to several standard synthetic manipulations in the synthesis of some monosaccharide targets. The protected monosaccharide 3 was readily permethylated using sodium hydride and methyl iodide (Scheme 2). Deprotection of the diacetal 6 in quantitative yield using trifluroacetic acid and water (9 1) at room temperature yielded methyl curamicoside 7 a component of everinomycin C 8 (Fig.1) which is a member of the orthosomycin family of antibiotics.5 These antibiotics feature several unusual monosaccharide components (Fig. 1) which were readily synthesised using this diacetal methodology. An added attractive aspect to the deprotection process was the volatility of the reaction byproducts leaving evaporation as the only purification process necessary. Returning to the synthetic manipulations selective iodination of the 6-hydroxy of 3 was possible by the procedure of Garegg and Samuelsson 6 allowing catalytic hydrogenation to convert the manno-configuration of 9 to a BDA protected rhamnopyranoside intermediate 10 (Scheme 2).Deprotection yielded methyl-a-D-rhamnopyranoside 11 the unnatural rhamnose configuration which is the main constituent of the Scheme 2 O O O OMe OH OH OMe OMe O O O OMe OMe OMe OMe OMe HO HO O OMe OMe OMe O O O OMe I OH OMe OMe O O O OMe OH OMe OMe HO HO O OMe OH O O O OMe O OMe OMe S SMe O O O OMe OMe OMe HO HO O OMe i. NaH ii. MeI DMF TFA:H2O (9:1) I2 PPh3 Imidazole Toluene heat H2 Pd/C Et2NH MeOH TFA:H2O (9:1) i. BuLi ii. CS2 iii. MeI THF Bu3SnH AIBN Toluene heat TFA:H2O (9:1) 3 6 7 11 9 10 12 13 14 86 94 99 85 86 75 73 85 2806 J. Chem. Soc. Perkin Trans. 1 1997 Scheme 3 O HO O OMe OMe MeO HO HO O OMe HO O O HO O OMe OMe MeO O I O HO O OMe OMe MeO O OH O MeO O OMe OMe MeO O HO MeO O OMe HO O O O OMe OMe MeO O S MeS O O OMe OMe MeO O HO O OMe HO I2 PPh3 Imidazole Toluene heat H2 Pd/C Et2NH MeOH i.BuLi ii. CS2 iii. MeI THF Bu3SnH AIBN Toluene heat TFA:H2O (9:1) i. NaH ii. MeI DMF TFA:H2O (9:1) TFA:H2O (9:1) 5 15 16 18 19 17 55 90 99 90 69 97 96 71 A-band lipopolysaccharide from the mutant Pseudomonas aeruginosa.7 The intermediate 10 was also converted to the xanthate ester 12 which on treatment with the conditions of Barton and McCombie yielded the 2-deoxygenated material 13.8 Hydrolysis of the diacetal yielded the 2-deoxyrhamnose structure 14 (Scheme 2) which is also a monosaccharide subunit found in certain orthosomycin antibiotics.5 The BDA protected galactose intermediate 5 proved equally as versatile in the synthesis of three further monosaccharides (Scheme 3). Once again it was available by the straightforward single step BDA protection of the parent monosaccharide 4 using the conditions illustrated (Scheme 1).2 Deoxygenation of the 6-position via iodination and hydrogenation led to the fuco-configured intermediate 15.Deprotection yielded the rarer D-configured methylfucopyranoside 16 in quantitative yield giving a monosaccharide 350 times as expensive as the starting D-galactopyranoside 4 in four steps. Returning to intermediate 15 methylation of the 4-hydroxy followed by deprotection yielded the 4-O-methylfucopyranoside 17 which is also found in everninomycin C (Fig. 1). As a final synthetic example of the BDA method formation of the xanthate ester at the 4-position of 15 by reaction of the Fig. 1 O O O O O O O O OH OH MeO O O O O O O O O HO OMe OMe O O O O OMe Cl OH Cl OMe O OMe NO2 Everninomycin C D-Mannose D-Mannose OH D-Galactose 8 alkoxide with carbon disulfide followed by methyl iodide allowed the Bartonndash;McCombie deoxygenation of the secondary position to take place.Direct access to this doubly deoxygenated pyranoside 18 via this method failed due to the difficulties in the breakdown of primary xanthates. The sequential deoxygenation strategy was therefore adopted. Deprotection of the diacetal unit under the standard conditions led to diol 19 which is an intermediate in Mitsunobursquo;s Grahamimycin A synthesis.9 In conclusion the protection pattern achieved rapidly by the use of 1,2-diacetal methodology allows facile interconversion of cheap monosaccharides to rarer expensive or commercially unavailable targets. The application of the method in the total synthesis of more structurally complex natural products is currently under investigation and will be reported in due course.The high yields obtained in the protection and deprotection of the BDA unit suggest that this may prove to be a versatile and strategic protecting group for use in synthesis. Acknowledgements We gratefully acknowledge financial support from the LINK Asymmetric Synthesis Programme (Studentship to D. R. O.) the Zeneca Strategic Research Fund and the Novartis Research Fellowship (to S. V. L.). References 1 P. Grice S. V. Ley J. Pietruszka and H. W. M. Priepke Angew. Chem. Int. Ed. Engl. 1996 35 197. 2 (a) N. L. Douglas S. V. Ley H. M. I. Osborne D. R. Owen H. W. M. Priepke and S. L. Warriner Synlett 1996 793; (b) A. Hense S. V. Ley H. M. I. Osborn D. R. Owen J.-F.Poisson S. L. Warriner and K. E. Wesson J. Chem. Soc. Perkin Trans. 1 1997 2023. 3 S. V. Ley and H. W. M. Priepke Angew. Chem. Int. Ed. Engl. 1994 33 2293. 4 V. Pozgay J.-R. Brisson and H. J. Jennings Can. J. Chem. 1987 65 2764. 5 D. E. Wright Tetrahedron 1979 35 1207. 6 P. J. Garegg and B. Samuelsson J. Chem. Soc. Perkin Trans. 1 1980 2866. 7 T. L. Arsenault D. B. MacLean W. Zou and W. A. Szarek Can. J. Chem. 1994 72 1376. 8 D. H. R. Barton and S. W. McCombie J. Chem. Soc. Perkin Trans. 1 1975 1574. 9 K. Ohta O. Miyagawa H. Tsutsui and O. Mitsunobu Bull. Chem. Soc. Jpn. 1993 66 523. Paper 7/05360F Received 24th July 1997 Accepted 8th August 1997 J. Chem. Soc. Perkin Trans. 1 1997 2805 Rapid access to rare natural pyranosides using 1,2-diacetal protected intermediates Steven V.Ley,* Dafydd R. Owen and Kieron E. Wesson Department of Chemistry University of Cambridge Lensfield Road Cambridge UK CB2 1EW The synthesis of six rare methylpyranosides from common manno- and galacto-pyranoside starting materials has been achieved by the expedient use of 1,2-diacetal protecting group methodology highlighting its compatibility with a number of other common synthetic procedures. The use of 1,2-diacetals as protecting groups for trans-1,2-diols has been shown to be a particularly useful method for the effi- cient construction of complex biologically significant oligosaccharides. 1 Recently several parameters for the design and exploitation of these 1,2-dione reagents for the direct protection of trans-1,2-diols have been established.2 Although relatively few 1,2-diones are effective in these reactions they have proved to be a versatile and powerful new protecting group protocol.The high selectivity for trans-1,2-diols in the presence of other polyols rapidly leads to protected monosaccharides amenable for further synthetic manipulation. The additional tuning effect on the latent glycosidation reactivity of these 1,2-diacetal protected building blocks in oligosaccharide assembly further enhances their synthetic utility.3 In this work we describe the high yielding selective protection reaction of methyl-a-D-mannopyranoside and methyl-a- D-galactopyranoside with butane-2,3-dione affording the cor- Scheme 1 i cat. CSA CH(OME)3 MeOH heat; ii cat. BF3?OEt2 CH(OMe)3 MeOH room temp. O O O O O OMe OH OH OMe OMe O HO HO OH OMe OH O O O HO O OMe OMe OMe O OH HO HO O OMe HO OH + 2 3 1 i.or ii. + 1 i. 95 ii. 99 80 4 5 i. responding butane-2,3-diacetal (BDA) intermediates which may be further manipulated in the expedient synthesis of some rare monosaccharides using a range of standard synthetic procedures. These reactions take place with no degradation or loss of the 1,2-diacetal protecting group. Typically the BDA intermediates such as 3 and 5 may be prepared by the direct reaction of butane-2,3-dione 1 which is both cheap and commercially available with the parent monosaccharide in the presence of catalytic camphorsulfonic acid (CSA) and trimethyl orthoformate in boiling methanol (Scheme 1).2 The protection reaction may also be carried out at room temperature in high yield using boron trifluoridendash;diethyl ether as a Lewis acid (Scheme 1).The highly crystalline BDA products need little further purification. The protection of the trans-1,2-diol in monosaccharide 2 in the presence of a cis-1,2- diol pair and 1,3-related pair makes this high yielding selective process highly attractive. The single step BDA procedure also eliminates several steps from conventional approaches to this level of protecting group selectivity.4 These BDA protected intermediates were subjected to several standard synthetic manipulations in the synthesis of some monosaccharide targets. The protected monosaccharide 3 was readily permethylated using sodium hydride and methyl iodide (Scheme 2). Deprotection of the diacetal 6 in quantitative yield using trifluroacetic acid and water (9 1) at room temperature yielded methyl curamicoside 7 a component of everinomycin C 8 (Fig.1) which is a member of the orthosomycin family of antibiotics.5 These antibiotics feature several unusual monosaccharide components (Fig. 1) which were readily synthesised using this diacetal methodology. An added attractive aspect to the deprotection process was the volatility of the reaction byproducts leaving evaporation as the only purification process necessary. Returning to the synthetic manipulations selective iodination of the 6-hydroxy of 3 was possible by the procedure of Garegg and Samuelsson 6 allowing catalytic hydrogenation to convert the manno-configuration of 9 to a BDA protected rhamnopyranoside intermediate 10 (Scheme 2). Deprotection yielded methyl-a-D-rhamnopyranoside 11 the unnatural rhamnose configuration which is the main constituent of the Scheme 2 O O O OMe OH OH OMe OMe O O O OMe OMe OMe OMe OMe HO HO O OMe OMe OMe O O O OMe I OH OMe OMe O O O OMe OH OMe OMe HO HO O OMe OH O O O OMe O OMe OMe S SMe O O O OMe OMe OMe HO HO O OMe i.NaH ii. MeI DMF TFA:H2O (9:1) I2 PPh3 Imidazole Toluene heat H2 Pd/C Et2NH MeOH TFA:H2O (9:1) i. BuLi ii. CS2 iii. MeI THF Bu3SnH AIBN Toluene heat TFA:H2O (9:1) 3 6 7 11 9 10 12 13 14 86 94 99 85 86 75 73 85 2806 J. Chem. Soc. Perkin Trans. 1 1997 Scheme 3 O HO O OMe OMe MeO HO HO O OMe HO O O HO O OMe OMe MeO O I O HO O OMe OMe MeO O OH O MeO O OMe OMe MeO O HO MeO O OMe HO O O O OMe OMe MeO O S MeS O O OMe OMe MeO O HO O OMe HO I2 PPh3 Imidazole Toluene heat H2 Pd/C Et2NH MeOH i. BuLi ii. CS2 iii. MeI THF Bu3SnH AIBN Toluene heat TFA:H2O (9:1) i.NaH ii. MeI DMF TFA:H2O (9:1) TFA:H2O (9:1) 5 15 16 18 19 17 55 90 99 90 69 97 96 71 A-band lipopolysaccharide from the mutant Pseudomonas aeruginosa.7 The intermediate 10 was also converted to the xanthate ester 12 which on treatment with the conditions of Barton and McCombie yielded the 2-deoxygenated material 13.8 Hydrolysis of the diacetal yielded the 2-deoxyrhamnose structure 14 (Scheme 2) which is also a monosaccharide subunit found in certain orthosomycin antibiotics.5 The BDA protected galactose intermediate 5 proved equally as versatile in the synthesis of three further monosaccharides (Scheme 3). Once again it was available by the straightforward single step BDA protection of the parent monosaccharide 4 using the conditions illustrated (Scheme 1).2 Deoxygenation of the 6-position via iodination and hydrogenation led to the fuco-configured intermediate 15.Deprotection yielded the rarer D-configured methylfucopyranoside 16 in quantitative yield giving a monosaccharide 350 times as expensive as the starting D-galactopyranoside 4 in four steps. Returning to intermediate 15 methylation of the 4-hydroxy followed by deprotection yielded the 4-O-methylfucopyranoside 17 which is also found in everninomycin C (Fig. 1). As a final synthetic example of the BDA method formation of the xanthate ester at the 4-position of 15 by reaction of the Fig. 1 O O O O O O O O OH OH MeO O O O O O O O O HO OMe OMe O O O O OMe Cl OH Cl OMe O OMe NO2 Everninomycin C D-Mannose D-Mannose OH D-Galactose 8 alkoxide with carbon disulfide followed by methyl iodide allowed the Bartonndash;McCombie deoxygenation of the secondary position to take place.Direct access to this doubly deoxygenated pyranoside 18 via this method failed due to the difficulties in the breakdown of primary xanthates. The sequential deoxygenation strategy was therefore adopted. Deprotection of the diacetal unit under the standard conditions led to diol 19 which is an intermediate in Mitsunobursquo;s Grahamimycin A synthesis.9 In conclusion the protection pattern achieved rapidly by the use of 1,2-diacetal methodology allows facile interconversion of cheap monosaccharides to rarer expensive or commercially unavailable targets. The application of the method in the total synthesis of more structurally complex natural products is currently under investigation and will be reported in due course.The high yields obtained in the protection and deprotection of the BDA unit suggest that this may prove to be a versatile and strategic protecting group for use in synthesis. Acknowledgements We gratefully acknowledge financial support from the LINK Asymmetric Synthesis Programme (Studentship to D. R. O.) the Zeneca Strategic Research Fund and the Novartis Research Fellowship (to S. V. L.). References 1 P. Grice S. V. Ley J. Pietruszka and H. W. M. Priepke Angew. Chem. Int. Ed. Engl. 1996 35 197. 2 (a) N. L. Douglas S. V. Ley H. M. I. Osborne D. R. Owen H. W. M. Priepke and S. L. Warriner Synlett 1996 793; (b) A. Hense S. V. Ley H. M. I. Osborn D. R. Owen J.-F. Poisson S. L. Warriner and K. E. Wesson J. Chem. Soc. Perkin Trans. 1 1997 2023. 3 S. V. Ley and H. W. M. Priepke Angew.Chem. Int. Ed. Engl. 1994 33 2293. 4 V. Pozgay J.-R. Brisson and H. J. Jennings Can. J. Chem. 1987 65 2764. 5 D. E. Wright Tetrahedron 1979 35 1207. 6 P. J. Garegg and B. Samuelsson J. Chem. Soc. Perkin Trans. 1 1980 2866. 7 T. L. Arsenault D. B. MacLean W. Zou and W. A. Szarek Can. J. Chem. 1994 72 1376. 8 D. H. R. Barton and S. W. McCombie J. Chem. Soc. Perkin Trans. 1 1975 1574. 9 K. Ohta O. Miyagawa H. Tsutsui and O. Mitsunobu Bull. Chem. Soc. Jpn. 1993 66 523. Paper 7/05360F Received 24th July 1997 Accepted 8th August 1997 J. Chem. Soc. Perkin Trans. 1 1997 2805 Rapid access to rare natural pyranosides using 1,2-diacetal protected intermediates Steven V. Ley,* Dafydd R. Owen and Kieron E. Wesson Department of Chemistry University of Cambridge Lensfield Road Cambridge UK CB2 1EW The synthesis of six rare methylpyranosides from common manno- and galacto-pyranoside starting materials has been achieved by the expedient use of 1,2-diacetal protecting group methodology highlighting its compatibility with a number of other common synthetic procedures.The use of 1,2-diacetals as protecting groups for trans-1,2-diols has been shown to be a particularly useful method for the effi- cient construction of complex biologically significant oligosaccharides. 1 Recently several parameters for the design and exploitation of these 1,2-dione reagents for the direct protection of trans-1,2-diols have been established.2 Although relatively few 1,2-diones are effective in these reactions they have proved to be a versatile and powerful new protecting group protocol.The high selectivity for trans-1,2-diols in the presence of other polyols rapidly leads to protected monosaccharides amenable for further synthetic manipulation. The additional tuning effect on the latent glycosidation reactivity of these 1,2-diacetal protected building blocks in oligosaccharide assembly further enhances their synthetic utility.3 In this work we describe the high yielding selective protection reaction of methyl-a-D-mannopyranoside and methyl-a- D-galactopyranoside with butane-2,3-dione affording the cor- Scheme 1 i cat. CSA CH(OME)3 MeOH heat; ii cat. BF3?OEt2 CH(OMe)3 MeOH room temp. O O O O O OMe OH OH OMe OMe O HO HO OH OMe OH O O O HO O OMe OMe OMe O OH HO HO O OMe HO OH + 2 3 1 i. or ii. + 1 i. 95 ii. 99 80 4 5 i. responding butane-2,3-diacetal (BDA) intermediates which may be further manipulated in the expedient synthesis of some rare monosaccharides using a range of standard synthetic procedures.These reactions take place with no degradation or loss of the 1,2-diacetal protecting group. Typically the BDA intermediates such as 3 and 5 may be prepared by the direct reaction of butane-2,3-dione 1 which is both cheap and commercially available with the parent monosaccharide in the presence of catalytic camphorsulfonic acid (CSA) and trimethyl orthoformate in boiling methanol (Scheme 1).2 The protection reaction may also be carried out at room temperature in high yield using boron trifluoridendash;diethyl ether as a Lewis acid (Scheme 1). The highly crystalline BDA products need little further purification. The protection of the trans-1,2-diol in monosaccharide 2 in the presence of a cis-1,2- diol pair and 1,3-related pair makes this high yielding selective process highly attractive.The single step BDA procedure also eliminates several steps from conventional approaches to this level of protecting group selectivity.4 These BDA protected intermediates were subjected to several standard synthetic manipulations in the synthesis of some monosaccharide targets. The protected monosaccharide 3 was readily permethylated using sodium hydride and methyl iodide (Scheme 2). Deprotection of the diacetal 6 in quantitative yield using trifluroacetic acid and water (9 1) at room temperature yielded methyl curamicoside 7 a component of everinomycin C 8 (Fig. 1) which is a member of the orthosomycin family of antibiotics.5 These antibiotics feature several unusual monosaccharide components (Fig.1) which were readily synthesised using this diacetal methodology. An added attractive aspect to the deprotection process was the volatility of the reaction byproducts leaving evaporation as the only purification process necessary. Returning to the synthetic manipulations selective iodination of the 6-hydroxy of 3 was possible by the procedure of Garegg and Samuelsson 6 allowing catalytic hydrogenation to convert the manno-configuration of 9 to a BDA protected rhamnopyranoside intermediate 10 (Scheme 2). Deprotection yielded methyl-a-D-rhamnopyranoside 11 the unnatural rhamnose configuration which is the main constituent of the Scheme 2 O O O OMe OH OH OMe OMe O O O OMe OMe OMe OMe OMe HO HO O OMe OMe OMe O O O OMe I OH OMe OMe O O O OMe OH OMe OMe HO HO O OMe OH O O O OMe O OMe OMe S SMe O O O OMe OMe OMe HO HO O OMe i.NaH ii. MeI DMF TFA:H2O (9:1) I2 PPh3 Imidazole Toluene heat H2 Pd/C Et2NH MeOH TFA:H2O (9:1) i. BuLi ii. CS2 iii. MeI THF Bu3SnH AIBN Toluene heat TFA:H2O (9:1) 3 6 7 11 9 10 12 13 14 86 94 99 85 86 75 73 85 2806 J. Chem. Soc. Perkin Trans. 1 1997 Scheme 3 O HO O OMe OMe MeO HO HO O OMe HO O O HO O OMe OMe MeO O I O HO O OMe OMe MeO O OH O MeO O OMe OMe MeO O HO MeO O OMe HO O O O OMe OMe MeO O S MeS O O OMe OMe MeO O HO O OMe HO I2 PPh3 Imidazole Toluene heat H2 Pd/C Et2NH MeOH i. BuLi ii. CS2 iii. MeI THF Bu3SnH AIBN Toluene heat TFA:H2O (9:1) i. NaH ii. MeI DMF TFA:H2O (9:1) TFA:H2O (9:1) 5 15 16 18 19 17 55 90 99 90 69 97 96 71 A-band lipopolysaccharide from the mutant Pseudomonas aeruginosa.7 The intermediate 10 was also converted to the xanthate ester 12 which on treatment with the conditions of Barton and McCombie yielded the 2-deoxygenated material 13.8 Hydrolysis of the diacetal yielded the 2-deoxyrhamnose structure 14 (Scheme 2) which is also a monosaccharide subunit found in certain orthosomycin antibiotics.5 The BDA protected galactose intermediate 5 proved equally as versatile in the synthesis of three further monosaccharides (Scheme 3).Once again it was available by the straightforward single step BDA protection of the parent monosaccharide 4 using the conditions illustrated (Scheme 1).2 Deoxygenation of the 6-position via iodination and hydrogenation led to the fuco-configured intermediate 15. Deprotection yielded the rarer D-configured methylfucopyranoside 16 in quantitative yield giving a monosaccharide 350 times as expensive as the starting D-galactopyranoside 4 in four steps.Returning to intermediate 15 methylation of the 4-hydroxy followed by deprotection yielded the 4-O-methylfucopyranoside 17 which is also found in everninomycin C (Fig. 1). As a final synthetic example of the BDA method formation of the xanthate ester at the 4-position of 15 by reaction of the Fig. 1 O O O O O O O O OH OH MeO O O O O O O O O HO OMe OMe O O O O OMe Cl OH Cl OMe O OMe NO2 Everninomycin C D-Mannose D-Mannose OH D-Galactose 8 alkoxide with carbon disulfide followed by methyl iodide allowed the Bartonndash;McCombie deoxygenation of the secondary position to take place. Direct access to this doubly deoxygenated pyranoside 18 via this method failed due to the difficulties in the breakdown of primary xanthates.The sequential deoxygenation strategy was therefore adopted. Deprotection of the diacetal unit under the standard conditions led to diol 19 which is an intermediate in Mitsunobursquo;s Grahamimycin A synthesis.9 In conclusion the protection pattern achieved rapidly by the use of 1,2-diacetal methodology allows facile interconversion of cheap monosaccharides to rarer expensive or commercially unavailable targets. The application of the method in the total synthesis of more structurally complex natural products is currently under investigation and will be reported in due course. The high yields obtained in the protection and deprotection of the BDA unit suggest that this may prove to be a versatile and strategic protecting group for use in synthesis.Acknowledgements We gratefully acknowledge financial support from the LINK Asymmetric Synthesis Programme (Studentship to D. R. O.) the Zeneca Strategic Research Fund and the Novartis Research Fellowship (to S. V. L.). References 1 P. Grice S. V. Ley J. Pietruszka and H. W. M. Priepke Angew. Chem. Int. Ed. Engl. 1996 35 197. 2 (a) N. L. Douglas S. V. Ley H. M. I. Osborne D. R. Owen H. W. M. Priepke and S. L. Warriner Synlett 1996 793; (b) A. Hense S. V. Ley H. M. I. Osborn D. R. Owen J.-F. Poisson S. L. Warriner and K. E. Wesson J. Chem. Soc. Perkin Trans. 1 1997 2023. 3 S. V. Ley and H. W. M. Priepke Angew. Chem. Int. Ed. Engl. 1994 33 2293. 4 V. Pozgay J.-R. Brisson and H. J. Jennings Can. J. Chem. 1987 65 2764. 5 D. E. Wright Tetrahedron 1979 35 1207.6 P. J. Garegg and B. Samuelsson J. Chem. Soc. Perkin Trans. 1 1980 2866. 7 T. L. Arsenault D. B. MacLean W. Zou and W. A. Szarek Can. J. Chem. 1994 72 1376. 8 D. H. R. Barton and S. W. McCombie J. Chem. Soc. Perkin Trans. 1 1975 1574. 9 K. Ohta O. Miyagawa H. Tsutsui and O. Mitsunobu Bull. Chem. Soc. Jpn. 1993 66 523. Paper 7/05360F Received 24th July 1997 Accepted 8th August 1997 J. Chem. Soc. Perkin Trans. 1 1997 2805 Rapid access to rare natural pyranosides using 1,2-diacetal protected intermediates Steven V. Ley,* Dafydd R. Owen and Kieron E. Wesson Department of Chemistry University of Cambridge Lensfield Road Cambridge UK CB2 1EW The synthesis of six rare methylpyranosides from common manno- and galacto-pyranoside starting materials has been achieved by the expedient use of 1,2-diacetal protecting group methodology highlighting its compatibility with a number of other common synthetic procedures.The use of 1,2-diacetals as protecting groups for trans-1,2-diols has been shown to be a particularly useful method for the effi- cient construction of complex biologically significant oligosaccharides. 1 Recently several parameters for the design and exploitation of these 1,2-dione reagents for the direct protection of trans-1,2-diols have been established.2 Although relatively few 1,2-diones are effective in these reactions they have proved to be a versatile and powerful new protecting group protocol. The high selectivity for trans-1,2-diols in the presence of other polyols rapidly leads to protected monosaccharides amenable for further synthetic manipulation.The additional tuning effect on the latent glycosidation reactivity of these 1,2-diacetal protected building blocks in oligosaccharide assembly further enhances their synthetic utility.3 In this work we describe the high yielding selective protection reaction of methyl-a-D-mannopyranoside and methyl-a- D-galactopyranoside with butane-2,3-dione affording the cor- Scheme 1 i cat. CSA CH(OME)3 MeOH heat; ii cat. BF3?OEt2 CH(OMe)3 MeOH room temp. O O O O O OMe OH OH OMe OMe O HO HO OH OMe OH O O O HO O OMe OMe OMe O OH HO HO O OMe HO OH + 2 3 1 i. or ii. + 1 i. 95 ii. 99 80 4 5 i. responding butane-2,3-diacetal (BDA) intermediates which may be further manipulated in the expedient synthesis of some rare monosaccharides using a range of standard synthetic procedures.These reactions take place with no degradation or loss of the 1,2-diacetal protecting group. Typically the BDA intermediates such as 3 and 5 may be prepared by the direct reaction of butane-2,3-dione 1 which is both cheap and commercially available with the parent monosaccharide in the presence of catalytic camphorsulfonic acid (CSA) and trimethyl orthoformate in boiling methanol (Scheme 1).2 The protection reaction may also be carried out at room temperature in high yield using boron trifluoridendash;diethyl ether as a Lewis acid (Scheme 1). The highly crystalline BDA products need little further purification. The protection of the trans-1,2-diol in monosaccharide 2 in the presence of a cis-1,2- diol pair and 1,3-related pair makes this high yielding selective process highly attractive.The single step BDA procedure also eliminates several steps from conventional approaches to this level of protecting group selectivity.4 These BDA protected intermediates were subjected to several standard synthetic manipulations in the synthesis of some monosaccharide targets. The protected monosaccharide 3 was readily permethylated using sodium hydride and methyl iodide (Scheme 2). Deprotection of the diacetal 6 in quantitative yield using trifluroacetic acid and water (9 1) at room temperature yielded methyl curamicoside 7 a component of everinomycin C 8 (Fig. 1) which is a member of the orthosomycin family of antibiotics.5 These antibiotics feature several unusual monosaccharide components (Fig. 1) which were readily synthesised using this diacetal methodology.An added attractive aspect to the deprotection process was the volatility of the reaction byproducts leaving evaporation as the only purification process necessary. Returning to the synthetic manipulations selective iodination of the 6-hydroxy of 3 was possible by the procedure of Garegg and Samuelsson 6 allowing catalytic hydrogenation to convert the manno-configuration of 9 to a BDA protected rhamnopyranoside intermediate 10 (Scheme 2). Deprotection yielded methyl-a-D-rhamnopyranoside 11 the unnatural rhamnose configuration which is the main constituent of the Scheme 2 O O O OMe OH OH OMe OMe O O O OMe OMe OMe OMe OMe HO HO O OMe OMe OMe O O O OMe I OH OMe OMe O O O OMe OH OMe OMe HO HO O OMe OH O O O OMe O OMe OMe S SMe O O O OMe OMe OMe HO HO O OMe i. NaH ii. MeI DMF TFA:H2O (9:1) I2 PPh3 Imidazole Toluene heat H2 Pd/C Et2NH MeOH TFA:H2O (9:1) i.BuLi ii. CS2 iii. MeI THF Bu3SnH AIBN Toluene heat TFA:H2O (9:1) 3 6 7 11 9 10 12 13 14 86 94 99 85 86 75 73 85 2806 J. Chem. Soc. Perkin Trans. 1 1997 Scheme 3 O HO O OMe OMe MeO HO HO O OMe HO O O HO O OMe OMe MeO O I O HO O OMe OMe MeO O OH O MeO O OMe OMe MeO O HO MeO O OMe HO O O O OMe OMe MeO O S MeS O O OMe OMe MeO O HO O OMe HO I2 PPh3 Imidazole Toluene heat H2 Pd/C Et2NH MeOH i. BuLi ii. CS2 iii. MeI THF Bu3SnH AIBN Toluene heat TFA:H2O (9:1) i. NaH ii. MeI DMF TFA:H2O (9:1) TFA:H2O (9:1) 5 15 16 18 19 17 55 90 99 90 69 97 96 71 A-band lipopolysaccharide from the mutant Pseudomonas aeruginosa.7 The intermediate 10 was also converted to the xanthate ester 12 which on treatment with the conditions of Barton and McCombie yielded the 2-deoxygenated material 13.8 Hydrolysis of the diacetal yielded the 2-deoxyrhamnose structure 14 (Scheme 2) which is also a monosaccharide subunit found in certain orthosomycin antibiotics.5 The BDA protected galactose intermediate 5 proved equally as versatile in the synthesis of three further monosaccharides (Scheme 3).Once again it was available by the straightforward single step BDA protection of the parent monosaccharide 4 using the conditions illustrated (Scheme 1).2 Deoxygenation of the 6-position via iodination and hydrogenation led to the fuco-configured intermediate 15. Deprotection yielded the rarer D-configured methylfucopyranoside 16 in quantitative yield giving a monosaccharide 350 times as expensive as the starting D-galactopyranoside 4 in four steps.Returning to intermediate 15 methylation of the 4-hydroxy followed by deprotection yielded the 4-O-methylfucopyranoside 17 which is also found in everninomycin C (Fig. 1). As a final synthetic example of the BDA method formation of the xanthate ester at the 4-position of 15 by reaction of the Fig. 1 O O O O O O O O OH OH MeO O O O O O O O O HO OMe OMe O O O O OMe Cl OH Cl OMe O OMe NO2 Everninomycin C D-Mannose D-Mannose OH D-Galactose 8 alkoxide with carbon disulfide followed by methyl iodide allowed the Bartonndash;McCombie deoxygenation of the secondary position to take place. Direct access to this doubly deoxygenated pyranoside 18 via this method failed due to the difficulties in the breakdown of primary xanthates. The sequential deoxygenation strategy was therefore adopted.Deprotection of the diacetal unit under the standard conditions led to diol 19 which is an intermediate in Mitsunobursquo;s Grahamimycin A synthesis.9 In conclusion the protection pattern achieved rapidly by the use of 1,2-diacetal methodology allows facile interconversion of cheap monosaccharides to rarer expensive or commercially unavailable targets. The application of the method in the total synthesis of more structurally complex natural products is currently under investigation and will be reported in due course. The high yields obtained in the protection and deprotection of the BDA unit suggest that this may prove to be a versatile and strategic protecting group for use in synthesis. Acknowledgements We gratefully acknowledge financial support from the LINK Asymmetric Synthesis Programme (Studentship to D.R. O.) the Zeneca Strategic Research Fund and the Novartis Research Fellowship (to S. V. L.). References 1 P. Grice S. V. Ley J. Pietruszka and H. W. M. Priepke Angew. Chem. Int. Ed. Engl. 1996 35 197. 2 (a) N. L. Douglas S. V. Ley H. M. I. Osborne D. R. Owen H. W. M. Priepke and S. L. Warriner Synlett 1996 793; (b) A. Hense S. V. Ley H. M. I. Osborn D. R. Owen J.-F. Poisson S. L. Warriner and K. E. Wesson J. Chem. Soc. Perkin Trans. 1 1997 2023. 3 S. V. Ley and H. W. M. Priepke Angew. Chem. Int. Ed. Engl. 1994 33 2293. 4 V. Pozgay J.-R. Brisson and H. J. Jennings Can. J. Chem. 1987 65 2764. 5 D. E. Wright Tetrahedron 1979 35 1207. 6 P. J. Garegg and B. Samuelsson J. Chem. Soc. Perkin Trans. 1 1980 2866. 7 T. L. Arsenault D. B. MacLean W. Zou and W. A. Szarek Can. J. Chem. 1994 72 1376. 8 D. H. R. Barton and S. W. McCombie J. Chem. Soc. Perkin Trans. 1 1975 1574. 9 K. Ohta O. Miyagawa H. Tsutsui and O. Mitsunobu Bull. Chem. Soc. Jpn. 1993 66 523. Paper 7/05360F Received 24th July 1997 Accepted 8th August 1997