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Pierre Gilles - One of the best experts on this subject based on the ideXlab platform.
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smi2 mediated cross coupling of nitrones with β silyl acrylates synthesis of Australine
ChemInform, 2012Co-Authors: Pierre GillesAbstract:The process affords the coupling products with nearly complete diastereoselection and can be used as key step in a new synthesis of (+)-Australine (VII).
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SmI2-Mediated Cross-Coupling of Nitrones with β-Silyl Acrylates: Synthesis of (+)-Australine.
ChemInform, 2012Co-Authors: Pierre GillesAbstract:The process affords the coupling products with nearly complete diastereoselection and can be used as key step in a new synthesis of (+)-Australine (VII).
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SmI2-Mediated Cross-Coupling of Nitrones with β-Silyl Acrylates: Synthesis of (+)-Australine
Organic Letters, 2012Co-Authors: Pierre GillesAbstract:The SmI2-mediated cross-coupling of nitrones with β-silyl-α,β-unsaturated esters, followed by zinc reduction, allows an efficient and highly diastereoselective preparation of β-silyl lactams, which are precursors of β-hydroxy lactams through Tamao–Fleming oxidation. By applying the method to a cyclic, carbohydrate-derived nitrone, a new synthesis of (+)-Australine has been realized in only 11 steps and in 21% overall yield from l-xylose.
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smi2 mediated cross coupling of nitrones with β silyl acrylates synthesis of Australine
Organic Letters, 2012Co-Authors: Pierre GillesAbstract:The SmI2-mediated cross-coupling of nitrones with β-silyl-α,β-unsaturated esters, followed by zinc reduction, allows an efficient and highly diastereoselective preparation of β-silyl lactams, which are precursors of β-hydroxy lactams through Tamao–Fleming oxidation. By applying the method to a cyclic, carbohydrate-derived nitrone, a new synthesis of (+)-Australine has been realized in only 11 steps and in 21% overall yield from l-xylose.
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Couplage croisé induit par SmI2 de nitrones avec des acrylates silylés : synthèse de Pyrrolizidines polyhydroxylées
2011Co-Authors: Pierre GillesAbstract:Les nitrones peuvent être réduites par le diiodure de samarium et réagir selon une additionconjuguée avec des acrylates-silylés, silylés ou ,disilylés. Ce couplage réducteur,développé avec des aldonitrones simples, a conduit à des dérivés silylés de g-Nhydroxyaminoacides.Ces derniers ont pu être réduits puis cyclisés en g-lactames substituéspar un groupement silylé, dont la position et la configuration dépendent de l’acrylate dedépart. L’oxydation de Tamao-Fleming a ensuite permis la conversion des composés silylésen leurs correspondants hydroxylés avec rétention de configuration. Cet enchaînementréactionnel a alors été appliquée à une nitrone cyclique polyalkoxylée dérivée du L-xylose, cequi a permis les synthèses de la 7-desoxy Uniflorine A et de la (+)-Australine, deuxpyrrolizidines polyhydroxylées inhibiteurs de glucosidases.
Peter Hrnciar - One of the best experts on this subject based on the ideXlab platform.
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synthesis of polyhydroxylated pyrrolizidine alkaloids of the alexine family by tandem ring closing metathesis transannular cyclization Australine
Journal of Organic Chemistry, 2000Co-Authors: James D White, Peter HrnciarAbstract:Dienes 23 and 54, prepared from epoxy alcohol 9 via oxazolidinones 15 and 51, respectively, underwent ring-closing metathesis with Grubbs's catalyst to give azacyclooctenes 26 and 55. Treatment of each azacyclooctene with m-chloroperoxybenzoic acid afforded β-epoxide 28 from 26 and α-epoxide 61 from 60. Basic hydrolysis of each of these oxazolidinones was accompanied by transannular attack at the epoxide by nitrogen, resulting in 2-(O-benzyl)-7-deoxyalexine (29) and 1,2-di-(O-benzyl)Australine (62). The latter was converted to the alkaloid Australine (3) upon hydrogenolysis. Attempts to effect ring-closing metathesis of dienes 37, 38, and 46 were unsuccessful, suggesting that, while one allylic oxygen substituent can be tolerated by Grubbs's catalyst, two cannot.
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Synthesis of polyhydroxylated pyrrolizidine alkaloids of the alexine family by tandem ring-closing metathesis-transannular cyclization. (+)-Australine.
The Journal of Organic Chemistry, 2000Co-Authors: James D White, Peter HrnciarAbstract:Dienes 23 and 54, prepared from epoxy alcohol 9 via oxazolidinones 15 and 51, respectively, underwent ring-closing metathesis with Grubbs's catalyst to give azacyclooctenes 26 and 55. Treatment of each azacyclooctene with m-chloroperoxybenzoic acid afforded β-epoxide 28 from 26 and α-epoxide 61 from 60. Basic hydrolysis of each of these oxazolidinones was accompanied by transannular attack at the epoxide by nitrogen, resulting in 2-(O-benzyl)-7-deoxyalexine (29) and 1,2-di-(O-benzyl)Australine (62). The latter was converted to the alkaloid Australine (3) upon hydrogenolysis. Attempts to effect ring-closing metathesis of dienes 37, 38, and 46 were unsuccessful, suggesting that, while one allylic oxygen substituent can be tolerated by Grubbs's catalyst, two cannot.
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Configurational and conformational analysis of highly oxygenated pyrrolizidines: definitive identification of some naturally occurring 7a-epi-alexines
Tetrahedron-asymmetry, 1998Co-Authors: Mark R. Wormald, Peter Hrnciar, Russell J. Molyneux, Robert J Nash, James D White, George W J FleetAbstract:Abstract The NMR spectra of a number of naturally occurring alexines (tetrahydroxylated pyrrolizidine alkaloids) are analyzed and the consequences of changes in the configuration on the conformation of these bicyclic systems discussed. Unambiguous syntheses of Australine (7-epi-alexine) and of 7,7a-epi-alexine have now unequivocally established the structures of two natural products isolated from Castanospermum australe which were insecure due to erroneous NMR data. Chemical shift parameters are unreliable as a method of comparing different samples of identical compounds; however, 1H–1H three bond coupling constants (3JHH) provide easy direct comparison between samples and allow assignments of both the relative configurations for the ring protons and the conformation of the pyrrolizidine framework.
James D White - One of the best experts on this subject based on the ideXlab platform.
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synthesis of polyhydroxylated pyrrolizidine alkaloids of the alexine family by tandem ring closing metathesis transannular cyclization Australine
Journal of Organic Chemistry, 2000Co-Authors: James D White, Peter HrnciarAbstract:Dienes 23 and 54, prepared from epoxy alcohol 9 via oxazolidinones 15 and 51, respectively, underwent ring-closing metathesis with Grubbs's catalyst to give azacyclooctenes 26 and 55. Treatment of each azacyclooctene with m-chloroperoxybenzoic acid afforded β-epoxide 28 from 26 and α-epoxide 61 from 60. Basic hydrolysis of each of these oxazolidinones was accompanied by transannular attack at the epoxide by nitrogen, resulting in 2-(O-benzyl)-7-deoxyalexine (29) and 1,2-di-(O-benzyl)Australine (62). The latter was converted to the alkaloid Australine (3) upon hydrogenolysis. Attempts to effect ring-closing metathesis of dienes 37, 38, and 46 were unsuccessful, suggesting that, while one allylic oxygen substituent can be tolerated by Grubbs's catalyst, two cannot.
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Synthesis of polyhydroxylated pyrrolizidine alkaloids of the alexine family by tandem ring-closing metathesis-transannular cyclization. (+)-Australine.
The Journal of Organic Chemistry, 2000Co-Authors: James D White, Peter HrnciarAbstract:Dienes 23 and 54, prepared from epoxy alcohol 9 via oxazolidinones 15 and 51, respectively, underwent ring-closing metathesis with Grubbs's catalyst to give azacyclooctenes 26 and 55. Treatment of each azacyclooctene with m-chloroperoxybenzoic acid afforded β-epoxide 28 from 26 and α-epoxide 61 from 60. Basic hydrolysis of each of these oxazolidinones was accompanied by transannular attack at the epoxide by nitrogen, resulting in 2-(O-benzyl)-7-deoxyalexine (29) and 1,2-di-(O-benzyl)Australine (62). The latter was converted to the alkaloid Australine (3) upon hydrogenolysis. Attempts to effect ring-closing metathesis of dienes 37, 38, and 46 were unsuccessful, suggesting that, while one allylic oxygen substituent can be tolerated by Grubbs's catalyst, two cannot.
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Configurational and conformational analysis of highly oxygenated pyrrolizidines: definitive identification of some naturally occurring 7a-epi-alexines
Tetrahedron-asymmetry, 1998Co-Authors: Mark R. Wormald, Peter Hrnciar, Russell J. Molyneux, Robert J Nash, James D White, George W J FleetAbstract:Abstract The NMR spectra of a number of naturally occurring alexines (tetrahydroxylated pyrrolizidine alkaloids) are analyzed and the consequences of changes in the configuration on the conformation of these bicyclic systems discussed. Unambiguous syntheses of Australine (7-epi-alexine) and of 7,7a-epi-alexine have now unequivocally established the structures of two natural products isolated from Castanospermum australe which were insecure due to erroneous NMR data. Chemical shift parameters are unreliable as a method of comparing different samples of identical compounds; however, 1H–1H three bond coupling constants (3JHH) provide easy direct comparison between samples and allow assignments of both the relative configurations for the ring protons and the conformation of the pyrrolizidine framework.
Jennifer V. Hines - One of the best experts on this subject based on the ideXlab platform.
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total syntheses of Australine and 7 epialexine
Journal of Organic Chemistry, 2000Co-Authors: William H. Pearson, Jennifer V. HinesAbstract:Three approaches were examined for the synthesis of 3-(hydroxymethyl)pyrrolizidines, a class of compounds that includes the polyhydroxylated pyrrolizidine alkaloids alexine (1), Australine (2), and various stereoisomers of thereof. In the first approach, the intramolecular cycloaddition of an azide onto an electron-rich 1, 3-diene bearing a terminal alkoxymethyl substituent (i.e., 21) afforded the dehydropyrrolizidines 22a and 22b, with 22a predominating. A rationale for this stereoselectivity was proposed. Transformation of the major diastereomer 22a into a natural 3-(hydroxymethyl)pyrrolizidine was not possible due to difficulties encountered in transforming the phenyl vinyl sulfide functionality into other useful functional groups. A second approach was examined, wherein the intramolecular cycloaddition of an azide with an optically pure S-t-Bu-substituted diene (i.e., 30) was found to produce the pyrrolizidine 31. In this case, the alkoxymethyl substituent was incorporated into the tether between the azide and the diene, rather than on the diene itself. A key transformation in the synthesis of the diene 30 was the use of the allylic borane R(2)BCH(2)CH=C(TMS)(StBu) for the stereoselective conversion of the D-arabinose-derived azido aldehyde 28 to the E-isomer of 30. The cyclization of 30 to 31 also produced the bicyclic triazene 32, the result of 1,3-dipolar cycloaddition of the azide onto the distal double bond of the diene. Again, difficulties in transformation of the vinyl sulfide functionality of 31 into useful oxygen functionality limited this approach to naturally occurring 3-(hydroxymethyl)pyrrolizidines. A third approach to these compounds was successful. The transformation of L-xylose into the azido epoxy tosylate 46 was accomplished using two Wittig reactions and an epoxidation, in addition to other standard functional group manipulations. Reductive double-cyclization of 46 afforded the pyrrolizidines 47a and 47b, which were debenzylated to afford (+)-Australine 2 and (-)-7-epialexine 4, respectively. In the preliminary report of this work, erroneous spectroscopic data in the original literature on the structural assignment of Australine led to the conclusion that the synthetic material obtained herein was actually (+)-7-epiAustraline. Recently corrected spectroscopic data have appeared which verify that (+)-Australine 2 was indeed synthesized for the first time.
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Total syntheses of (+)-Australine and (-)-7-epialexine.
The Journal of Organic Chemistry, 2000Co-Authors: William H. Pearson, Jennifer V. HinesAbstract:Three approaches were examined for the synthesis of 3-(hydroxymethyl)pyrrolizidines, a class of compounds that includes the polyhydroxylated pyrrolizidine alkaloids alexine (1), Australine (2), and various stereoisomers of thereof. In the first approach, the intramolecular cycloaddition of an azide onto an electron-rich 1, 3-diene bearing a terminal alkoxymethyl substituent (i.e., 21) afforded the dehydropyrrolizidines 22a and 22b, with 22a predominating. A rationale for this stereoselectivity was proposed. Transformation of the major diastereomer 22a into a natural 3-(hydroxymethyl)pyrrolizidine was not possible due to difficulties encountered in transforming the phenyl vinyl sulfide functionality into other useful functional groups. A second approach was examined, wherein the intramolecular cycloaddition of an azide with an optically pure S-t-Bu-substituted diene (i.e., 30) was found to produce the pyrrolizidine 31. In this case, the alkoxymethyl substituent was incorporated into the tether between the azide and the diene, rather than on the diene itself. A key transformation in the synthesis of the diene 30 was the use of the allylic borane R(2)BCH(2)CH=C(TMS)(StBu) for the stereoselective conversion of the D-arabinose-derived azido aldehyde 28 to the E-isomer of 30. The cyclization of 30 to 31 also produced the bicyclic triazene 32, the result of 1,3-dipolar cycloaddition of the azide onto the distal double bond of the diene. Again, difficulties in transformation of the vinyl sulfide functionality of 31 into useful oxygen functionality limited this approach to naturally occurring 3-(hydroxymethyl)pyrrolizidines. A third approach to these compounds was successful. The transformation of L-xylose into the azido epoxy tosylate 46 was accomplished using two Wittig reactions and an epoxidation, in addition to other standard functional group manipulations. Reductive double-cyclization of 46 afforded the pyrrolizidines 47a and 47b, which were debenzylated to afford (+)-Australine 2 and (-)-7-epialexine 4, respectively. In the preliminary report of this work, erroneous spectroscopic data in the original literature on the structural assignment of Australine led to the conclusion that the synthetic material obtained herein was actually (+)-7-epiAustraline. Recently corrected spectroscopic data have appeared which verify that (+)-Australine 2 was indeed synthesized for the first time.
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A synthesis of (+)-7-EpiAustraline and (−)-7-Epialexine
Tetrahedron Letters, 1991Co-Authors: William H. Pearson, Jennifer V. HinesAbstract:Reducttve cycliration of the aztdo epoxides 19a and 19/3followed by &protection afforded the HN rnkbttor (+)-7-eptatutraline 7 ar(d (-)-'l-epialextne 9. The formatwn of 7 proceeded with an unusual tnverston of configuratton at C-7. Polyhydroxylated indolizidine alkaloids such as castanospermine 1 and swainsonine 2 have attracted considerable interest in recent years due to their ability to inhibit glycosidases.1 In addition to their use in the study of glycoprotein-processing enzymes, such alkaloids are promising anticancer and antrretrovnal agents. More recently, polyhydroxylated pyrrolizidine alkaloids with similar biological activities have emerged from the independent investigations of research teams in the U.K. and the U.S.A. The isolation of alexine 3 from Alexa leiopetala was reported in 1988.2 The isolation of similar alkaloids from Castanospetmwn australe quickly followed, including 3,7a-diepialexine (or 3-epiAustraline) 4,3,4 Australine 5,5 I-epiAustraline (or 1,7a- dieptalexine) 6,6*7 and 7,7a-diepialexme (or 7-epiAustraline) 7 .7 While alexine 3 and 3-eptAustraline 4 are generally poor inhibitors of glucosidases and galactosidases,*,4 they display a m lo y g lucostdase inhibition which is on par with that of castanospermine,7 and alexine is an effective thioglucosidase inhibitor.8 Compounds 5-7 are also good amyloglucosidase inhibitors. 5,779 Australine 5 inhibits glucosidase I, but not glucosidase II,9 and has recently been shown to exhibit antiviral activity. 10 Modest glucosidase I, g-glucosidase, and rx-mannosidase inhibition was observed for I-epiAustraline 6.6 but it displayed good acttvity in a mouse gut digestive a- glucosidase assay, as did 7-epiaustmliie 7. 7.11 An exciting recent report shows that australme 5, l- epiAustraline 6, and 7-epiAustraline 7 inhibit HIV-induced syncytia formation in N cells1 1 The potential of the polyhydroxylated pyrrolizidine alkaloids as selective glycosidase inhibitors and as antiviral and antiretrovtral agents makes them attractive targets for synthesis. In particular, the ability to prepare alternative stereoisomers of these alkaloids would be desirable, since the biological activity of these compounds varies substantially with their stereochemistry. We wish to report our initial efforts in this area, which have led to the synthesis of the naturally occurring alkaloid (+)-7-epiAustraline 7 (also known as 7,7a_diepialexme) which shows anti-HIV
Tsutomu Ishikawa - One of the best experts on this subject based on the ideXlab platform.
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Enantioselective construction of a polyhydroxylated pyrrolidine skeleton from 3-vinylaziridine-2-carboxylates: synthesis of (+)-DMDP and a potential common intermediate for (+)-hyacinthacine A1 and (+)-1-epi-Australine.
The Journal of Organic Chemistry, 2012Co-Authors: Yukari Kondo, Noriyuki Suzuki, Masato Takahashi, Takuya Kumamoto, Hyuma Masu, Tsutomu IshikawaAbstract:We report an enantioselective synthesis of the polyhydroxylated pyrrolidine alkaloid (+)-DMDP. The key steps in the synthesis were guanidinium ylide mediated asymmetric aziridination, stereospecific ring opening of trans-3-vinylaziridine-2-carboxylate with an oxygen nucleophile, iodine-mediated 5-endo-trig amino cyclization, and Prevost displacement. In addition, a potential common intermediate for the polyhydroxylated pyrrolizidine alkaloids (+)-hyacinthacine A(1) and (+)-1-epi-Australine was synthesized from a diastereoisomeric cis-aziridine coformed in the asymmetric aziridination using the same strategy. A rationale for the diastereoselectivity observed for the iodine-mediated amino cyclization reactions is proposed on the basis of the heats of formation of the products.
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enantioselective construction of a polyhydroxylated pyrrolidine skeleton from 3 vinylaziridine 2 carboxylates synthesis of dmdp and a potential common intermediate for hyacinthacine a1 and 1 epi Australine
Journal of Organic Chemistry, 2012Co-Authors: Yukari Kondo, Noriyuki Suzuki, Masato Takahashi, Takuya Kumamoto, Hyuma Masu, Tsutomu IshikawaAbstract:We report an enantioselective synthesis of the polyhydroxylated pyrrolidine alkaloid (+)-DMDP. The key steps in the synthesis were guanidinium ylide mediated asymmetric aziridination, stereospecific ring opening of trans-3-vinylaziridine-2-carboxylate with an oxygen nucleophile, iodine-mediated 5-endo-trig amino cyclization, and Prevost displacement. In addition, a potential common intermediate for the polyhydroxylated pyrrolizidine alkaloids (+)-hyacinthacine A(1) and (+)-1-epi-Australine was synthesized from a diastereoisomeric cis-aziridine coformed in the asymmetric aziridination using the same strategy. A rationale for the diastereoselectivity observed for the iodine-mediated amino cyclization reactions is proposed on the basis of the heats of formation of the products.
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Enantioselective Construction of a Polyhydroxylated Pyrrolidine Skeleton from 3‑Vinylaziridine-2-carboxylates: Synthesis of (+)-DMDP and a Potential Common Intermediate for (+)-Hyacinthacine A1 and (+)-1-epi-Australine
2012Co-Authors: Yukari Kondo, Noriyuki Suzuki, Masato Takahashi, Takuya Kumamoto, Hyuma Masu, Tsutomu IshikawaAbstract:We report an enantioselective synthesis of the polyhydroxylated pyrrolidine alkaloid (+)-DMDP. The key steps in the synthesis were guanidinium ylide mediated asymmetric aziridination, stereospecific ring opening of trans-3-vinylaziridine-2-carboxylate with an oxygen nucleophile, iodine-mediated 5-endo-trig amino cyclization, and Prévost displacement. In addition, a potential common intermediate for the polyhydroxylated pyrrolizidine alkaloids (+)-hyacinthacine A1 and (+)-1-epi-Australine was synthesized from a diastereoisomeric cis-aziridine coformed in the asymmetric aziridination using the same strategy. A rationale for the diastereoselectivity observed for the iodine-mediated amino cyclization reactions is proposed on the basis of the heats of formation of the products
