First total synthesis and absolute configuration of naturally occurring (−)-hyacinthacine A7 and its (−)-1-epi-isomer

Izquierdo, Isidoro; Plaza, Marı́a T.; Tamayo, Juan A.; Yáñez, Víctor; Re, Daniele Lo; Sánchez-Cantalejo, Fernando

doi:10.1016/j.tet.2008.03.009

Cited by 21 publications

(5 citation statements)

References 39 publications

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“… [a] Compounds of this work and references to others with identical relative stereochemistry at C1, C2, C3, and C7a: 9 a and 9 f ,19, 27 9 b and 9 e ,29, 30 9 c , 9 h and 9 i ,20, 22, 26, 27, 31 9 d and 9 j ,17 9 k ,18, 22 9 l 27. [b] Data from a previous study 7.…”

Section: Resultsmentioning

confidence: 99%

Structure‐Guided Minimalist Redesign of the L‐Fuculose‐1‐Phosphate Aldolase Active Site: Expedient Synthesis of Novel Polyhydroxylated Pyrrolizidines and their Inhibitory Properties Against Glycosidases and Intestinal Disaccharidases

Garrabou

Gómez

Joglar

et al. 2010

Chemistry A European J

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A minimalist active site redesign of the L-fuculose-1-phosphate aldolase from E. coli FucA was envisaged, to extend its tolerance towards bulky and conformationally restricted N-Cbz-amino aldehyde acceptor substrates (Cbz=benzyloxycarbonyl). Various mutants at the active site of the FucA wild type were obtained and screened with seven sterically demanding N-Cbz-amino aldehydes including N-Cbz-prolinal derivatives. FucA F131A showed an aldol activity of 62 μmol h(-1) mg(-1) with (R)-N-Cbz-prolinal, whereas no detectable activity was observed with the FucA wild type. For the other substrates, the F131A mutant gave aldol activities from 4 to about 25 times higher than those observed with the FucA wild type. With regard to the stereochemistry of the reactions, the (R)-amino aldehydes gave exclusively the anti configured aldol adducts whereas their S counterparts gave variable ratios of anti/syn diastereoisomers. Interestingly, the F131A mutant was highly stereoselective both with (R)- and with (S)-N-Cbz-prolinal, exclusively producing the anti and syn aldol adducts, respectively. Molecular models suggest that this improved activity towards bulky and more rigid substrates, such as N-Cbz-prolinal, could arise from a better fit of the substrate into the hydrophobic pocket created by the F131A mutation, due to an additional π-cation interaction with the residue K205' and to efficient contact between the substrate and the mechanistically important Y113' and Y209' residues. An expedient synthesis of novel polyhydroxylated pyrrolizidines related to the hyacinthacine and alexine types was accomplished through aldol additions of dihydroxyacetone phosphate (DHAP) to hydroxyprolinal derivatives with the hyperactive FucA F131A as catalyst. The iminocyclitols obtained were fully characterised and found to be moderate to weak inhibitors (relative to 1,4-dideoxy-1,4-imino-L-arabinitol (LAB) and 1,4-dideoxy-1,4-imino-D-arabinitol (DAB)) against glycosidases and rat intestinal saccharidases.

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Section: Resultsmentioning

confidence: 99%

Structure‐Guided Minimalist Redesign of the L‐Fuculose‐1‐Phosphate Aldolase Active Site: Expedient Synthesis of Novel Polyhydroxylated Pyrrolizidines and their Inhibitory Properties Against Glycosidases and Intestinal Disaccharidases

Garrabou

Gómez

Joglar

et al. 2010

Chemistry A European J

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“…Compound 17 was synthesized from the tricyclic ketone 16 (28 mg, 0.0640 mmol) by using the general method for the reduction of a ketone to a secondary alcohol with L-Selectride. The product was purified by FCC ( 5 (1R,2S,3R,5R,6R,7S,7aR)-6-Benzyloxy-5-[(benzyloxy)methyl]-3methylhexahydro-1H-pyrrolizine-1,2,7-triol (18). Compound 18 was synthesized from 17 (18.5 mg, 0.0421 mmol) using the general method for hydrolysis of an acetonide.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…The hyacinthacine alkaloids display a range of glycosidase inhibitory activities, leading to a number of reports detailing their total synthesis. − Structurally, the hyacinthacine C-type subclass of these alkaloids is the most diverse subclass of hyacinthacine and has recently generated synthetic interest. ,,,− They can contain up to seven possible stereogenic centers, which means that there are 128 unique possible stereoisomers containing a 3-hydroxymethyl-5-methylpyrrolizidine-1,2,6,7-tetraol core that can be potentially synthesized. Their high degree of oxidation and analogous structure to glucose make this class a particularly enticing but challenging target for synthetic chemists interested in the preparation of therapeutic iminosugars.…”

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confidence: 99%

Corrected Structure of Natural Hyacinthacine C₁ via Total Synthesis

et al. 2019

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Hyacinthacines C 1 and C 4 are natural products that were isolated from Hyacinthoides non-scripta and Scilla socialis in 1999 and 2007, respectively. Despite their different 1 H NMR and 13 C NMR spectroscopic data, these compounds have been assigned the same structures, including absolute configurations. This work details the total synthesis of natural (+)-hyacinthacine C 1 , whose structure is confirmed as being the C-6 epimer of that reported. The synthetic strategy focused on inverting the configuration at C-1 of the final hyacinthacines via operating the inversion at the corresponding carbon atom in three previously synthesized intermediates. To do this, the advanced intermediates were subjected to Swern oxidation, followed by a stereoselective reduction with L-Selectride. This approach led to the synthesis of (+)-5-epi-hyacinthacine C 1 (15), the corrected structure for (+)-hyacinthacine C 1 ( 19), (+)-6,7-di-epi-hyacinthacine C 1 (23), and (+)-7-epi-hyacinthacine C 1 (29). Glycosidase inhibition assays revealed that (+)-hyacinthacine C 1 (19) proved the most active, with IC 50 values of 33.7, 55.5, and 78.2 μM, against the α-glucosidase of rice, human lysosome, and rat intestinal maltase, respectively.

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“…To date, fourteen of the natural hyacinthacines, A 1 , A 2 , A 3 , A 6 , A 7 , B 1 , B 2 , B 3 , B 4 , B 5 , B 7 , C 2 , C 3 and C 5 have been synthesized, along with their related epimers and enantiomers. [51][52][53][54][55][56][57][58][59][60][61][62][63][64] At this point, the authors note that an increasing number of reports suggest the confirmation of hyacinthacine A 5 through methods of total synthesis. [61,63,65] To the best of our knowledge, hyacinthacine A 5 has not yet been synthesized and although epimers of the structure have been reported, [66] the absolute configuration of the natural isolate is still yet to be confirmed.…”

Section: Current Issues With the Hyacinthacine Alkaloidsmentioning

confidence: 99%

The History of the Glycosidase Inhibiting Hyacinthacine C-type Alkaloids: From Discovery to Synthesis.

Carroll

Pyne

2019

COS

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Background: The inherent glycosidase inhibitory activity and potentially therapeutic value of the polyhydroxylated pyrrolizidine alkaloids containing a hydroxymethyl substituent at the C-3 position have been well documented. Belonging to this class, the naturally occurring hyacinthacine C-type alkaloids are of general interest among iminosugar researchers. Their selective micromolar α -glycosidase inhibitory ranges (10 – 100 μM) suggest that these azasugars are potential leads for treating type II diabetes. However, the structures of hyacinthacine C1, C3 and C4 are insecure with hyacinthacine C5 being recently corrected. Objective: This review presents the hyacinthacine C-type alkaloids: their first discovery to the most recent advancements on the structures, biological activities and total synthesis. Conclusion: The hyacinthacine C-type alkaloids are of exponentially increasing interest and will undoubtedly continue to be reported as synthetic targets. They represent a challenging but rewarding synthetic feat for the community of those interested in accessing biologically active iminosugars. Since 2009, ten total syntheses have been employed towards accessing similarly related products but only three have assessed the glycosidase inhibitory activity of the final products. This suggests the need for an accessible and universal glycosidase inhibitory assay so to accurately determine the structure-activity relationship of how the hyacinthacine C-type alkaloids inhibit specific glycosidases. Confirming the correct structures of the hyacinthacine C-type alkaloids as well as accessing various analogues continues to strengthen the foundation towards a marketable treatment for type II diabetes and other glycosidase related illnesses.

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First total synthesis and absolute configuration of naturally occurring (−)-hyacinthacine A7 and its (−)-1-epi-isomer

Cited by 21 publications

References 39 publications

Structure‐Guided Minimalist Redesign of the L‐Fuculose‐1‐Phosphate Aldolase Active Site: Expedient Synthesis of Novel Polyhydroxylated Pyrrolizidines and their Inhibitory Properties Against Glycosidases and Intestinal Disaccharidases

Structure‐Guided Minimalist Redesign of the L‐Fuculose‐1‐Phosphate Aldolase Active Site: Expedient Synthesis of Novel Polyhydroxylated Pyrrolizidines and their Inhibitory Properties Against Glycosidases and Intestinal Disaccharidases

Corrected Structure of Natural Hyacinthacine C₁ via Total Synthesis

The History of the Glycosidase Inhibiting Hyacinthacine C-type Alkaloids: From Discovery to Synthesis.

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First total synthesis and absolute configuration of naturally occurring (−)-hyacinthacine A7 and its (−)-1-epi-isomer

Cited by 21 publications

References 39 publications

Structure‐Guided Minimalist Redesign of the L‐Fuculose‐1‐Phosphate Aldolase Active Site: Expedient Synthesis of Novel Polyhydroxylated Pyrrolizidines and their Inhibitory Properties Against Glycosidases and Intestinal Disaccharidases

Structure‐Guided Minimalist Redesign of the L‐Fuculose‐1‐Phosphate Aldolase Active Site: Expedient Synthesis of Novel Polyhydroxylated Pyrrolizidines and their Inhibitory Properties Against Glycosidases and Intestinal Disaccharidases

Corrected Structure of Natural Hyacinthacine C1 via Total Synthesis

The History of the Glycosidase Inhibiting Hyacinthacine C-type Alkaloids: From Discovery to Synthesis.

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Corrected Structure of Natural Hyacinthacine C₁ via Total Synthesis