Synthesis of Aryl C-Glycosides via Iron-Catalyzed Cross Coupling of Halosugars: Stereoselective Anomeric Arylation of Glycosyl Radicals.

We have developed a novel diastereoselective iron-catalyzed cross-coupling reaction of various glycosyl halides with aryl metal reagents for the efficient synthesis of aryl C-glycosides, which are of significant pharmaceutical interest due to their biological activities and resistance toward metabolic degradation. A variety of aryl, heteroaryl, and vinyl metal reagents can be cross-coupled with glycosyl halides in high yields in the presence of a well-defined iron complex, composed of iron(II) chloride and a bulky bisphosphine ligand, TMS-SciOPP. The chemoselective nature of the reaction allows the use of synthetically versatile acetyl-protected glycosyl donors and the incorporation of various functional groups on the aryl moieties, producing a diverse array of aryl C-glycosides, including Canagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), and a prevailing diabetes drug. The cross-coupling reaction proceeds via generation and stereoselective trapping of glycosyl radical intermediates, representing a rare example of highly stereoselective carbon-carbon bond formation based on iron catalysis. Radical probe experiments using 3,4,6-tri-O-acetyl-2-O-allyl-α-d-glucopyranosyl bromide (8) and 6-bromo-1-hexene (10) confirm the generation and intermediacy of the corresponding glycosyl radicals. Density functional theory (DFT) calculations reveal that the observed anomeric diastereoselectivity is attributable to the relative stability of the conformers of glycosyl radical intermediates. The present cross-coupling reaction demonstrates the potential of iron-catalyzed stereo- and chemoselective carbon-carbon bond formation in the synthesis of bioactive compounds of certain structural complexity.

Concise and Stereodivergent Synthesis of Carbasugars Reveals Unexpected Structure-Activity Relationship (SAR) of SGLT2 Inhibition.

Carbasugar sodium-glucose cotransporter 2 (SGLT2) inhibitors are highly promising drug candidates for the treatment of Type 2 diabetes mellitus (T2DM). However, the clinical usage of carbasugar SGLT2 inhibitors has been underexplored, due to the lengthy synthetic routes and the lack of structure-activity relationship (SAR) studies of these compounds. Herein, we report a concise and stereodivergent synthetic route towards some novel carbasugar SGLT2 inhibitors, featuring an underexploited, regioselective, and stereospecific palladium-catalyzed allyl-aryl coupling reaction. This synthetic strategy, together with computational modeling, revealed the unexpected SAR of these carbasugar SGLT2 inhibitors, and enabled the discovery of a highly selective and potent SGLT2 inhibitor.

Palladium-Catalyzed Arylation of Carbasugars Enables the Discovery of Potent and Selective SGLT2 Inhibitors.

Selective inhibition of the transporter protein sodium-glucose cotransporter 2 (SGLT2) has emerged as a promising way to control blood glucose level in diabetes patients. Reported herein is a short and convergent synthetic route towards some small-molecule SGLT2 inhibitors by a chemo- and diastereospecific palladium-catalyzed arylation reaction. This synthetic strategy enabled the discovery of two highly selective and potent SGLT2 inhibitors, thereby paving the way towards the development of carbasugar SGLT2 inhibitors as potential antidiabetic/antitumor agents.

Intramolecular direct aldol reactions of sugar 2,7-diketones: syntheses of hydroxylated cycloalka(e)nones.

A regio- and stereoselective intramolecular direct aldol reaction of 2,7-diketones derived from carbohydrates has been developed to construct cycloalkanones , which were dehydrated to obtain heavily oxygenated cycloalkenones .

Syntheses of arabinose-derived pyrrolidine catalysts and their applications in intramolecular Diels-Alder reactions.

Six chiral hydroxylated pyrrolidine catalysts were synthesized from commercially available D-arabinose in seven steps. Various aromatic substituents α to the amine can be introduced readily by a Grignard reaction, which enables facile optimization of the catalyst performance. The stereoselectivities of these catalysts have been assessed by comparing with those of MacMillan's imidazolidinone in a known intramolecular Diels-Alder (IMDA) reaction of a triene. Two additional IMDA reactions of symmetrical dienals with concomitant desymmetrisation further established the potential use of these novel amine catalysts. These pyrrolidines are valuable catalysts for other synthetic transformations.

Conformationally locked bicyclo[4.3.0]nonane carbanucleosides: synthesis and bio-evaluation.

D-Ribose was converted into 3 novel carbobicyclic nucleosides bearing a bicyclo[4.3.0]nonane framework in 16-19 steps with 5-12% overall yields involving a Wittig olefination and an intramolecular Diels-Alder reaction as the key steps. The present synthesis also provides an efficient entry for chiral hydrindenones. The conformation studies of these carbanucleosides and their bio-evaluation as potential antiviral agents are reported.

Synthesis of chiral hydroxylated enones as potential anti-tumor agents.

A series of chiral hydroxylated enones were synthesized as COTC ether analogues to investigate the structural features required for optimal and selective anti-tumor activity. The cytotoxicity of the seven COTC ether analogues against WRL-68 normal and HepG2, HL-60 cancer cell lines were measured. C-4 ether analogues with an aliphatic chain substituent were found to be more favorable than their aromatic counterparts. Inversion of the configuration at C-4 in 5e to give 5f only resulted in reduced selectivity towards cancer cells. These results show that 4-O-pentyl-gabosine D (5e) has optimum selectivity and cytotoxicity towards two cancer cell lines.

Inhibition of glutathione S-transferase M1 by new gabosine analogues is essential for overcoming cisplatin resistance in lung cancer cells.

A new class of human GST inhibitors has been identified via rational design approach; we report their discovery, synthesis, inhibitory activity, and synergetic effect in combination with cisplatin against A549 lung cancer cell line. The results of this effort show that the lead 4-O-decyl-gabosine D (24) has optimum synergetic effect in A549 human lung adenocarcinoma epithelial cell and that this activity involves inhibition of glutathione S-transferase M1, apparently consistent with siRNA-mediated knockdown of GSTM1 gene.

Facile and enantiospecific syntheses of (6S,7R)-6-chloro-7-benzyloxy-, (7S)-halo-, and (7S)-hydroxy-cocaine and natural (-)-cocaine from D-(-)-ribose.

First syntheses of C6,7 and C7 enantiopure cocaine analogues were achieved from D-(-)-ribose via a trans-acetonide controlled endo-selective intramolecular nitrone-alkene cycloaddition (INAC) as the key step. This synthetic scheme allows practical preparation of cocaine analogues for bioevaluation as potential candidates for the treatment of cocaine addiction and as potential conjugates for immunotherapy.

An alternative synthesis of 1,1'-bis-valienamine from D-glucose.

An alternative synthesis of 1,1'-bis-valienamine 5, which was demonstrated to be a potent trehalase inhibitor, has been achieved from d-glucose in 12 steps with 15% overall yield via enone 12 as the key intermediate, involving a direct aldol reaction of a glucose-derived diketone and a palladium-catalyzed allylic coupling reaction as the key steps.

Facile syntheses of (+)-gabosines A, D, and E.

(+)-Gabosines A (12), D (4), and E (5), which share the same trihydroxycyclohexenone skeleton, were synthesized from enone 11 as the common intermediate. The key building block 11 was accessed by an intramolecular aldol cyclization of a diketone derived from D-glucose (8).

Carbocyclization of carbohydrates: diastereoselective synthesis of (+)-gabosine F, (-)-gabosine O, and (+)-4-epi-gabosine O.

Exploitation of silica gel/chloramine T mediated intramolecular nitrile oxide-alkene cycloaddition (INOC) of sugar-derived oximes to carbocycles furnished the first synthesis of gabosine F from l-arabinose in 12 steps with 23% overall yield, thereby confirming its absolute configuration. Similarly, efficient syntheses of gabosine O and 4-epi-gabosine O were accomplished from D-mannose in 9 and 11 steps with 41% and 38% overall yields, respectively, involving INOC, regioselective dehydration, and diastereoselective hydrogenation as the key steps.

Stereo- and regioselectivity in an intramolecular nitrone-alkene cycloaddition of hept-6-enoses with a trans-acetonide blocking group.

From sugar to cycloadduct: The effect of the trans-acetonide blocking group and the stereochemistry of the substituents on the regio- and stereoselectivity in the intramolecular nitrone-alkene cycloaddition (INAC) reaction of hept-6-enoses (see scheme) is reported and studied by using theoretical analysis.The positional effect of the trans-acetonide blocking group and the effect of the stereochemistry of the substituents on the regio- and stereoselectivity in intramolecular nitrone-alkene cycloaddition (INAC) reactions of hept-6-enoses are reported. Hept-6-enoses with a 2,3-trans-acetonide group were reacted with N-alkyl hydroxylamine to give a mixture of exo and endo cycloadducts (cyclohexanols and cycloheptanols, respectively). Complete formation of endo cycloadducts (cycloheptanols) was realized for the INAC reaction of hept-6-enoses containing a 3,4-trans-O-isopropylidene ring. Similarly, reaction of a hept-6-enose possessing a 4,5-trans-acetonide group surprisingly afforded exo cycloadducts (cyclohexanols) exclusively. The regio- and stereochemical outcomes of these reactions were rationalized on the basis of transition-state energies obtained by computation.

Intramolecular direct aldol reactions of sugar diketones: syntheses of valiolamine and validoxylamine G.

A new and stereoselective intramolecular direct aldol reaction of diketones derived from carbohydrates has been developed to construct carbocycles with D-gluco-, D-galacto-, D-manno-, and L-ido-configurations. The stereochemical outcome of the aldol reaction of the diketone is dependent on the base used. Transformation of D-gluco-aldols readily affords valiolamine which also constitutes a formal synthesis of voglibose. Facile conversion of D-gluco-cyclohexanones into validoxylamine G has been achieved in 12 steps with 15.1% overall yield from D-glucose.

Enantiospecific synthesis of pseudoacarviosin as a potential antidiabetic agent.

A pseudo-1,4'- N-linked disaccharide, pseudoacarviosin 5, was constructed via a key palladium-catalyzed coupling reaction of pseudoglycosyl chloride 8 (prepared from d-glucose via a novel direct intramolecular aldol addition in 12 steps) and pseudo-4-amino-4,6-dideoxy-alpha- d-glucose 9 (prepared from l-arabinose via an unusual trans-fused isoxazolidine-selective intramolecular nitrone-alkene cycloaddition in 11 steps). Pseudoacarviosin 5 has been shown to be a potent inhibitor of alpha-glucosidases, particularly the intestinal mucosal enzymes sucrase and glucoamylase of relevance to blood glucose control.

Short syntheses of gabosine I and gabosine G from delta-D-gluconolactone.

A short synthesis of gabosine I (1) from delta-D-gluconolactone (3) in four steps, involving a one-pot TPAP oxidation-K2CO3-mediated intramolecular Horner-Wadsworth-Emmons (HWE) olefination as the key step, is described. Regioselective acetylation of the primary alcohol in gabosine I (1) then furnished gabosine G (2).

Intramolecular nitrile oxide-alkene cycloaddition of sugar derivatives with unmasked hydroxyl group(s).

[reaction: see text] Intramolecular nitrile oxide-alkene cycloaddition (INOC) of sugar derivatives with one to four free hydroxyl group(s) is reported. The INOC reaction, using chloramine-T, in the presence of silica gel, to generate nitrile oxides from oximes, proceeded smoothly to afford five- or six-membered carbocycles in good to excellent yields. This new methodology alleviates protection/deprotection steps and makes the synthetic route shorter and more efficient.

trans-acetonide controlled endo-selective intramolecular nitrone-alkene cycloaddition of hept-6-enoses: a facile entry to calystegines, tropanes, and hydroxylated aminocycloheptanes.

High-yielding endo-selective intramolecular nitrone-alkene cycloaddition (INAC) reactions of hept-6-enoses controlled by a trans-acetonide to give bridged bicyclo[4.2.1]isoxazolidines exclusively are realized for the first time. The cycloadducts were readily transformed into calystegine, tropane, and hydroxylated aminocycloheptane frameworks. [reaction: see text].

Synthetic studies towards pentacyclic quassinoids: total synthesis of unnatural (-)-14-epi-samaderine E and natural (-)-samaderine Y from (S)-(+)-carvone.

First total syntheses of unnatural (-)-14-epi-samaderine E (5) and natural (-)-samaderine Y (2) were accomplished from (S)-(+)-carvone (6) in 18 and 21 steps, respectively. The syntheses are short, efficient (with an average yield of 80 % plus for each transformation), enantiospecific, and produce nine new chiral centers. The crucial points of the syntheses included a regioselective allylic oxidation on ring C, regio- and stereoselective reduction of ketone, a stereocontrolled epoxidation, an epoxymethano-bridge formation, a chemoselective Grignard reaction, an intramolecular Diels-Alder reaction, an intramolecular aldol addition, and a newly developed manganese(III)-catalyzed allylic oxidation on ring A.