Polyhydroxylated pyrrolidines: synthesis from d-fructose of new tri-orthogonally protected 2,5-dideoxy-2,5-iminohexitols

Izquierdo, Isidoro; Plaza, Marı́a T.; Yáñez, Víctor

doi:10.1016/j.tet.2006.11.070

Cited by 19 publications

(16 citation statements)

References 28 publications

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“…13,14 d -Fructose ( 15 ) was protected with acetone to give 1,2:4,5-di- O -acetonide (16) . Alcohol 16 was benzylated at the OH-3 position to afford protected d -(+)-fructose ( 17 ).…”

Section: Resultsmentioning

confidence: 99%

“…The reaction of 20 with modified Garegg’s conditions caused the substitution of the hydroxyl group at C-5 with iodine by inversion of configuration to give the corresponding 4- O -benzoyl-3- O -benzyl-5-deoxy-5-iodo-1,2- O -isopropylidene-α- l -sorbopyranose (21) . 13 Compound 21 was subjected to an S N 2 substitution reaction with sodium azide in N , N -dimethylformamide to give product 22 with 90% yield. Finally, the deprotection of the benzoyl group at OH-4 was achieved using Zemplén conditions to afford 23 (Scheme 3).…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of a Poly-hydroxypyrolidine-Based inhibitor of Mycobacterium tuberculosis GlgE

et al. 2014

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Long treatment times, poor drug compliance, and natural selection during treatment of Mycobacterium tuberculosis (Mtb) have given rise to extensively drug-resistant tuberculosis (XDR-TB). As a result, there is a need to identify new antituberculosis drug targets. Mtb GlgE is a maltosyl transferase involved in α-glucan biosynthesis. Mutation of GlgE in Mtb increases the concentration of maltose-1-phosphate (M1P), one substrate for GlgE, causing rapid cell death. We have designed 2,5-dideoxy-3-O-α-d-glucopyranosyl-2,5-imino-d-mannitol (9) to act as an inhibitor of GlgE. Compound 9 was synthesized using a convergent synthesis by coupling thioglycosyl donor 14 and 5-azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (23) to form disaccharide 24. A reduction and intramolecular reductive amination transformed the intermediate disaccharide 24 to the desired pyrolidine 9. Compound 9 inhibited both Mtb GlgE and a variant of Streptomyces coelicolor (Sco) GlgEI with Ki = 237 ± 27 μM and Ki = 102 ± 7.52 μM, respectively. The results confirm that a Sco GlgE-V279S variant can be used as a model for Mtb GlgE. In conclusion, we designed a lead transition state inhibitor of GlgE, which will be instrumental in further elucidation of the enzymatic mechanism of Mtb GlgE.

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“…13,14 d -Fructose ( 15 ) was protected with acetone to give 1,2:4,5-di- O -acetonide (16) . Alcohol 16 was benzylated at the OH-3 position to afford protected d -(+)-fructose ( 17 ).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis of a Poly-hydroxypyrolidine-Based inhibitor of Mycobacterium tuberculosis GlgE

et al. 2014

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“…In this context, in recent years our group has put into practice a synthetic methodology consisting of the use of commercial D-fructose as homochiral starting material for the preparation of orthogonally protected tetrahydroxylated pyrrolidines. 17,18 Such protection allows the easy chemical manipulation of the free As shown in Scheme 1, reaction of (2S,3R,4R,5R)-4-(benzoyloxy)-3-(benzyloxy)-1-(benzyloxycarbonyl)-2-[(tertbutyldiphenylsilyloxy)methyl]-5-(hydroxymethyl)pyrrolidine (9) 17 under Garegg's conditions 19 gave the corresponding 5-iodomethyl derivative 10. Catalytic hydrogenation of 10 with Raney nickel 20 resulted in dehalogenation concomitant with partial N-deprotection which was finally achieved after further hydrogenation over 10% palladium on carbon to afford 11.…”

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confidence: 99%

Polyhydroxylated Pyrrolidines: Synthesis of Trideoxy-2,5-iminohexitols

Izquierdo¹,

Plaza²,

Tamayo³

et al. 2008

Synthesis

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A series of naturally occurring pyrrolidine alkaloids and analogues, with the general structure of trideoxy-2,5-iminohexitols (imino-or azasugars), have been enantiosynthesized using triorthogonally protected pyrrolidines, previously prepared from commercial D-fructose, as homochiral starting materials. The inhibitory activity of some of the described compounds against glycosidases and glycosyltransferases makes them potential therapeutic agents.In 1991 Wong and co-workers 2 described, for the first time, a synthetic methodology that combined an enzymatic aldol condensation reaction, giving a key intermediate 5-azido-5-deoxyhexulose, with a highly stereocontrolled intramolecular reductive amination, which afforded a trihydroxylated pyrrolidine identified as 2,5,6-trideoxy-2,5-imino-D-glucitol (6-deoxy-DGDP, 1). Two years later, 3 Wong's group, using the same methodology, reported the synthesis of 1 as well as of three new trideoxy-2,5-iminohexitols, named as 1,2,5-trideoxy-2,5-imino-D-glucitol (1-deoxy-DGDP, 2), 1,2,5-trideoxy-2,5-imino-L-altritol (ent-4 = 5), and 1,2,5-trideoxy-2,5-imino-D-mannitol (1-deoxy-DMDP, 7) 4 (see Figure 1). Compound 7 was isolated in the same year by Molyneux and co-workers from seeds 5 of Angylocalyx pynaertii (Leguminosae) and more recently, together with compounds 3 and 4, from the bark 6 and pods 7 of this plant. The structure and absolute configuration of 7 was confirmed by an unambiguous synthesis from diacetone D-glucose. 5 Bisseret and co-workers 8 reported a new synthesis of 7 using lithiation of an aziridine ring, whereas a highly diastereoselective reductive benzyloxymethylation of protected tartarimide was the methodology chosen by Huang and co-workers 9 in order to achieve the synthesis of 7. Compound 2 has also been synthesized by Lee and Jeong 10 from commercial D-glucurono-d-lactone and by Clapés and co-workers, 11 together with 3, 5, 2,5,6-trideoxy-2,5-imino-D-altritol (6-deoxy-DALDP, 6), 7, and ent-7 (= 8), through an enzymatic reaction similar to that mentioned above. Pyrrolidines 4 and 6 were also prepared by Defoin and co-workers 12 from chiral 1,2-oxazines, while the former has recently been described by Moriarty and co-workers who employed an exo-to endo-iminocyclitol rearrangement. 13 Compound 7 was shown to be a moderate competitive inhibitor versus b-mannosidase (IC 50 380 mM), 5 as well as a potent inhibitor of bovine epididymis a-L-fucosidase (IC 50 150 mM), rat epididymis b-mannosidase (IC 50 93 mM), and bovine liver b-galactosidase (IC 50 30 mM). 6,

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“…Compound 10 was obtained after a treatment with 50% trifluoroacetic acid (TFA) at room temperature instead of 70% acetic acid. 25 …”

Section: Results and Discussionmentioning

confidence: 99%

Introducing Lipophilicity to (Polyhydroxyalkyl)thiazolidine Carboxylic Acids Via Acylation

et al. 2022

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The therapeutic efficacy of bioactive compounds is related to their bioavailability. In turn, the bioavailability depends on the equilibrium between the hydrophilicity and the lipophilicity. 2( R,S )-(Polyhydroxyalkyl)thiazolidine-4( R ) carboxylic acids (TCAs), obtained from the condensation of l -cysteine and an aldose, have been recognized as nontoxic precursors of glutathione with important preventive and therapeutic effects. The bioavailability of these compounds can be improved by enhancing their lipophilicity. This can be achieved by the introduction of some acyl groups derived from fatty acids via esterification of the aldose hydroxyl groups. With this purpose four new compounds were synthesized through a selective palmitoyl acylation of d -(−)-ribose and d -(+)-glucose and subsequent condensation with l -cysteine. In addition, the log P of the new compounds was calculated as a measure of the lipophilicity, and in vitro 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) tests were performed as a measure of the antioxidant capability.

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Polyhydroxylated pyrrolidines: synthesis from d-fructose of new tri-orthogonally protected 2,5-dideoxy-2,5-iminohexitols

Cited by 19 publications

References 28 publications

Synthesis of a Poly-hydroxypyrolidine-Based inhibitor of Mycobacterium tuberculosis GlgE

Synthesis of a Poly-hydroxypyrolidine-Based inhibitor of Mycobacterium tuberculosis GlgE

Polyhydroxylated Pyrrolidines: Synthesis of Trideoxy-2,5-iminohexitols

Introducing Lipophilicity to (Polyhydroxyalkyl)thiazolidine Carboxylic Acids Via Acylation

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