- Scale-up synthesis of swainsonine: A potent #-mannosidase II inhibitor
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The large-scale synthesis of Swainsonine 1, a potent α-mannosidase II inhibitor, has been achieved with several improvements. The key modifications were (a) performing the Wittig olefination under mild conditions and isolation of the product 4 with modified workup conditions, (b) introduction of the azido group on a large scale under Mitsunobu conditions to produce 12, (c) performing the 1,3-dipolar cycloaddition of an unactivated azide 12 to afford the imino carboxylic ester 7, (d) formation of amide 10 from 7 under mild acidic conditions, and (e) isolation of the final compound 1 as a stable hydrochloride salt. In addition, synthesis of 11 was accomplished from 12 by telescoping the four steps.
- Sharma, Pradeep K.,Shah, Rajan N.,Carver, Jeremy P.
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- (1S,2R,8aS)-1,2-Dihydroxyindolizidine Formation by Rhizoctania leguminicola, the Fungus That Produces Slaframine and Swainsonine
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The title diol (6a) has been shown to be a metabolite of Rhizoctonia leguminicola, the fungus that produces two toxic indolizidine alkaloids, swainsonine (1) and slaframine (2).The structure of 6a was established spectroscopically and confirmed by synthesis of both C-8a epimers 6a and 7a.The absolute configuration was inferred from the efficient reutilization of the isolated 6a to form 1.Diol 7a could not be detected among the products of fermentation.It is noteworthy that 6a is probably an intermediate in the biosynthesis of swainsonine although it differs from the alkaloid in being epimeric at the 8a position
- Harris, Thomas M.,Harris, Constance M.,Hill, James E.,Ungemach, Frank S.,Broquist, Harry P.,Wickwire, Brian M.
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- Intramolecular 5-endo-trig aminopalladation of β-hydroxy-γ- alkenylamine: Efficient route to a pyrrolidine ring and its application for the synthesis of (-)-8,8a-di-epi-swainsonine
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The intramolecular aminopalladation reaction of l-serine derived β-hydroxy-γ-alkenylamines undergoes 5-endo-trig cyclization to furnish pyrrolidine rings in high yields. The pyrrolidines thus obtained were used in the synthesis of (-)-8,8a-di-epi-swainsonine, a specific and competitive inhibitor (Ki value 2 × 10-6 M) of lysosomal α-mannosidases.
- Singh, Priyanka,Panda, Gautam
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p. 2161 - 2166
(2014/01/06)
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- A flexible enantioselective approach to 3,4-dihydroxyprolinol derivatives by SmI2-mediated reductive coupling of chiral nitrone with ketones/aldehydes
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A flexible enantioselective approach to polyhydroxylated prolinol derivatives was described, which is based on the samarium diiodide-mediated reductive coupling of the chiral nitrone (3S,4R)-8, derived from d-isoascorbic acid with aldehydes/ketones. Thereby, polyhydroxyprolinol derivatives 9a-e and 9h-j were obtained from aromatic ketones and aliphatic aldehydes in good to excellent yields of 65-91%. These reductive hydroxyalkylations are highly diastereoselective in establishing the C-4 stereogenic center. By this way, the asymmetric syntheses of (-)-8a-epi-swainsonine (4) and (-)-8,8a-di-epi- swainsonine (5) have been achieved.
- Zhang, Hong-Kui,Xu, Shou-Qiang,Zhuang, Jia-Jia,Ye, Jian-Liang,Huang, Pei-Qiang
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experimental part
p. 6656 - 6664
(2012/08/29)
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- Nitrenium ion-mediated alkene bis-cyclofunctionalization: Total synthesis of (-)-swainsonine
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Chemical equations presented. The total synthesis of (-)-swainsonine from 2,3-O-isopropylidene-d-erythrose in 12 steps and an overall yield of 28% is reported. The pivotal transformation in our route to this indolizidine alkaloid is the formation of the pyrrolidine ring and C-8a/8 stereodiad through the diastereoselective, bis-cyclofunctionalization of an γ,ss-unsaturated O-alkyl hydroxamate. This transformation is believed to proceed via the intramolecular capture of an N-acyl-N-alkoxyaziridinium ion generated by the diastereoselective addition of a singlet acylnitrenium ion to the pendant alkene.
- Wardrop, Duncan J.,Bowen, Edward G.
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p. 2376 - 2379
(2011/06/22)
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- Concise and divergent total synthesis of swainsonine, 7-alkyl swainsonines, and 2,8a-diepilentiginosine via a chiral heterocyclic enaminoester intermediate
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The concise and divergent total syntheses of (-)-swainsonine, (-)-7-alkyl swainsonines, and (-)-2,8a-diepilentiginosine from a common chiral heterocyclic enaminoester intermediate in five-step sequences are presented. The highly efficient annulation reaction of the chiral heterocyclic enaminoester with various α,β-unsaturated carboxylates, and a straightforward carboxy inversion constituted the key features of the synthetic pathway. This work provides an example for divergent synthesis of different natural and unnatural polyhydroxylated indolizidines from a readily available platform.
- Shi, Gao-Feng,Li, Jia-Qi,Jiang, Xiao-Ping,Cheng, Ying
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p. 5005 - 5012
(2008/09/21)
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- De novo asymmetric syntheses of d-, l- and 8-epi-d-swainsonine
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A highly enantioselective and stereocontrolled approach to d-, l- and 8-epi-d-swainsonine has been developed from achiral furan and γ-butyrolactone. A one-pot hydrogenolysis of both azide and benzyl ether followed by an intramolecular reductive amination has been employed as key step to establish the indolizidine ring system. The absolute stereochemistry was installed by the Noyori reduction and the relative stereochemistry by the use of several highly diastereoselective palladium-catalyzed glycosylation, Luche reduction, dihydroxylation, and palladium-catalyzed azide allylation reactions. This practical approach provide multigram quantities of indolizidine natural product d-swainsonine in 13 steps and 25% overall yield.
- Guo, Haibing,O'Doherty, George A.
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p. 304 - 313
(2008/04/01)
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- Enantioselective ring expansion of prolinol derivatives. Two formal syntheses of (-)-swainsonine
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Two enantioselective formal syntheses of (-)-swainsonine have been achieved from l-proline by using an enantioselective ring enlargement of substituted prolinols as the key step. The more efficient synthesis has been achieved in 14 steps with an overall yield of 14%.
- Déchamps, Ingrid,Pardo, Domingo Gomez,Cossy, Janine
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p. 9082 - 9091
(2008/03/12)
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- De novo asymmetric synthesis of D- and L-swainsonine
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The enantioselective syntheses of both enantiomers of the indolizidine natural product swainsonine have been achieved in 13 steps from furan. The indolizidine ring system is installed by a one-pot hydrogenolysis of both an azide and an O-Bn group along with an intramolecular reductive amination reaction. The asymmetry of swainsonine was introduced by Noyori reduction of an acylfuran. This route relies upon an Achmatowicz rearrangement, a diastereoselective palladium-catalyzed glycosylation, Luche reduction, and a dihydroxylation reaction.
- Guo, Haibing,O'Doherty, George A.
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p. 1609 - 1612
(2007/10/03)
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- Asymmetric synthesis of (-)-swainsonine, (+)-1,2-di-epi-swainsonine, and (+)-1,2,8-tri-epi-swainsonine
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The asymmetric synthesis of (-)-swainsonine via a nonchiral pool route that involves the Sharpless epoxidation to induce chirality is reported. The key steps involve vinyl epoxide aminolysis, ring-closing metathesis, and intramolecular N-alkylation to prepare the indolizidine ring and a highly diastereoselective cis-dihydroxylation using AD-mix-α. This synthetic strategy also allowed for the diastereoselective synthesis of (+)-1,2-di-epi-swainsonine and (+)-1,2,8-tri-epi-swainsonine.
- Lindsay, Karl B.,Pyne, Stephen G.
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p. 7774 - 7780
(2007/10/03)
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- Allylated monosaccharides as precursors in triple reductive amination strategies: Synthesis of castanospermine and swainsonine
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The feasibility of the triple-reductive amination reaction for the synthesis of complex indolizidine frameworks is illustrated by application to the potent glycosidase inhibitors castanospermine and swainsonine. The target compounds were obtained from known carbohydrate precursors in yields of 23 and 14%, over nine and 13 steps, respectively. The iodoetherification reaction of allylated monosaccharides was shown to be a practical reaction for the synthesis of the tricarbonyl precursors for the key triple reductive amination reactions.
- Zhao,Hans,Cheng,Mootoo
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p. 1761 - 1767
(2007/10/03)
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- Stereocontrolled Synthesis of trans-3-Hydroxypipecolic Acids and Application to (-)-Swainsonine
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The enantioselective synthesis of both enantiomers of trans-3-hydroxypipecolic acid are described from a prochiral starting material: the methyl 3-oxo-7-methyloct-6-enoate.The stereocenters of the piperidine ring are created by enantioselective hydrogenation of the β-ketoester and by diastereoselective electrophilic amination of the β-hydroxyester enolate. (2R,3R)-3-Hydroxypipecolic acid methyl ester is the precursor for the synthesis of (-)-swainsonine. - Keywords: piperidine; indolizidine; chiral ruthenium complex; electrophilic amination.
- Ferreira, Franck,Greck, Christine,Genet, Jean Pierre
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p. 615 - 622
(2007/10/03)
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- An enantiocontrolled synthesis of (-)-Swainsonine
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(-)-Swainsonine 1, first isolated from the fungus Rhizoctonia leguminicola, has been sythesized enantioseletively. The key step was the stereoselective iodoamination of trichloro- acetimidate derived from (Z)- olefinic allylic alcohol 7.
- Kang, Sung Ho,Kim, Geun Tae
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p. 5049 - 5052
(2007/10/02)
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- Diisopropyl tartrate-modified (E)-γ-[(menthofuryl)dimethylsilyl]-allyl boronate, an improved chiral reagent for the anti α-hydroxyallylation of aldehydes. Application to the enantioselective synthesis of (-)-swainsonine
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An enantioselective synthesis of anti 1,2-diols via the reactions of aldehydes and the tartrate ester-modified (E)-γ-(menthofurylsilyl)allylboronate 5 has been developed. This methodology is applied to a brief, enantioselective synthesis of (-)-swainsonine.
- Hunt,Roush
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p. 501 - 504
(2007/10/02)
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- Enantioselective Synthesis of Indolizidine Alkaloids: Formal Synthesis of (-)-Swainsonine and of (+)-Pumiliotoxin 251 D
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Oxidative treatment of optically active 2-furylmethanol (furfuryl alcohol) derivative (R)-5, obtained by Sharpless kinetic resolution of the racemate, afforded the pyranone 9, which on successive reduction with lithium aluminium hydride in the presence of
- Honda, Toshio,Hoshi, Michiyasu,Kanai, Kazuo,Tsubuki, Masayoshi
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p. 2091 - 2102
(2007/10/02)
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- New Chiral Route to (-)-Swainsonine via an Aqueous Acylnitroso Cycloaddition Approach
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A new noncarbohydrate-based enantioselective approach to (-)-swainsonine (1) is described, in which the aqueous intramolecular Diels-Alder reaction of a chiral acylnitroso diene has been employed as a key reaction.The intramolecular cycloaddition of the chiral hydroxamic acid 9, available from D-malic acid in 10 steps, with Pr4NIO4 was conducted under the conventional nonaqueous conditions using CHCl3 as a solvent, whereupon intermediacy acylnitroso compound 10 cyclized spontaneously to give the trans- and cis-1,2-oxazinolactams 11 and 12 with a low diastereoselection af 1.3:1 in 76percent combined yield.When the corresponding reaction was performed in water, it led to significant enhancements of trans selectivity of 4.1:1 as well as combined yield (89percent).The trans adduct 11 was subjected to reductive N-O bond cleavage followed by diastereoselective hydroxylation with OsO4 to provide the 1,2-glycol 21, which was then converted to the amino alcohol 25.Intramolecular cyclodehydration of 25 with CBr4/PPh3/Et3N and subsequent deprotection furnished (-)-swainsonine (1).
- Naruse, Masaichi,Aoyagi, Sakae,Kibayashi, Chihiro
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p. 1358 - 1364
(2007/10/02)
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- An Acylnitroso Cycloaddition Approach to the Synthesis of Highly Oxygenated Indolizidine Alkaloids
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A synthetic approach to the synthesis of highly oxygenated indolizidine alkaloids is described.A key feature of the approach is intramolecular cycloaddition between an acylnitroso dienophile and a tethered diene moiety, followed by ring contraction of the 1,2-oxazine so formed to a pyrrolidine.The requisite intermediates were prepared in optically pure form from L-glutamic acid.
- Keck, Gary E.,Romer, Duane R.
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p. 6083 - 6089
(2007/10/02)
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- The intramolecular cycloaddition of azides with ω-chloroalkenes. A facile route to (-)-swainsonine and other indolizidine alkaloids
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A potentially general route to the 1-azabicyclo[n.m.0]alkane skeleton of various alkaloids is embodied in the intramolecular 1,3-dipolar cycloaddition of aliphatic azides with ω-chloroalkenes. Cycloaddition is followed by rearrangement and intramolecular N-alkylation, affording bicyclic iminium ions 1 in one operation. The application of this method to the synthesis of (±)-δ-coniceine 6, (1S,2R,8aR)-indolizidine-1,2-diol 13 and (-)-swainsonine 15 is described.
- Pearson,Lin
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p. 7571 - 7574
(2007/10/02)
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- A Short, Enantioselective Synthesis of (-)-Swainsonine
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A practical, enantioselective synthesis of (-)-swainsonine (1) has been achieved in seven steps from 2,3-O-isopropylidene-D-erythorose (6).The key step involves the construction of the bicyclic imine 4 by an intramolecular 1,3 dipolar cycloaddition of azide 5.This study highlights the synthetic utility of the intramolecular 1,3 dipolar cycloaddition of the unactivated olefinic azides in natural product synthesis.
- Bennett, Richard B.,Choi, Jong-Ryoo,Montgomery, Walter D.,Cha, Jin K.
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p. 2580 - 2582
(2007/10/02)
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- SYNTHESIS OF THE α-MANNOSIDASE INHIBITORS SWAINSONINE AND 1,4-DIDEOXY-1,4-IMINO-D-MANNITOL FROM MANNOSE
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4-azido-4-deoxy-2,3-O-isopropylidene-α-D-mannopyranoside is a key intermediate in the syntheses of the α-mannosidase inhibitors, swainsonine and 1,4-dideoxy-1,4-imino-D-mannitol, and of the α-galactosidase inhibitor 1,4-dideoxy-1,4-imino-D-lyxitol, from mannose.
- Bashyal, Bharat P.,Fleet, George W. J.,Gough, Max J.,Smith, Paul W.
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p. 3083 - 3094
(2007/10/02)
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- Enantiospecific Total Synthesis of (-)-Swainsonine: New Aplications of Sodium Borohydride Reduction
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A short, enantiospecific synthesis of (-)-swainsonine (1) from D-mannose has been achieved by a route involving, as a key step, a double cyclization of 4c.The synthesis takes adventage of new features of sodium borohydride for reducing conjugated esters and lactams.
- Setoi, Hiroyuki,Takeno, Hidekazu,Hashimoto, Masashi
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p. 3948 - 3950
(2007/10/02)
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- ENANTIOSPECIFIC SYNTHESIS OF SWAINSONINE, (1S, 2R, 8R, 8aR)-1,2,8-TRIHYDROXYOCTAHYDROINDOLIZINE, FROM D-MANNOSE
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An enantiospecific synthesis of swainsonine from D-mannose is described; the heterocyclic rings of swainsonine are constructed by two intramolecular reductive aminations caused by the catalytic hydrogenation of an azidoaldehyde with 5 equivalents of hydrogen.
- Fleet, G. W. J.,Gough, M. J.,Smith, P. W.
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p. 1853 - 1856
(2007/10/02)
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