The first total synthesis of glycyrol

We report the first total synthesis of glycyrol. Glycyrol, isolated from Glycyrrhizae Radix, has a unique skeleton of a benzofuran coumarin. The key steps are Smiles rearrangement and selective introduction of prenyl and O-methyl groups. The first application of a novel precursor for Smiles rearrangement, 3-benzyloxy-substituted (diacetoxyiodo)benzene, showed the synthetic possibility for diverse precursors. The introduction of a benzyl protecting group was important because selective deprotection was hard due to the low solubility of intermediates.     

Claisen rearrangements—VI : Synthesis of the coumarins,sesibiricin and toddaculin

The natural coumarins, sesibiricin (1) and toddaculin (28) have been synthesised from 5,7-dihydroxycoumarin, the former by a sequence involving regioselective O-prenylation at C-5 and C-prenylation at C-8. The prenyl ether of 5-hydroxy-7-methoxycoumarin, a key intermediate in the synthesis of toddaculin, has been found to undergo Claisen rearrangement exclusively to the para position thereby providing an alternative route to sesibiricin.     

Synthesis of poinsettifolin A

A synthesis of poinsettifolin A (1), a prenylated flavonol isolated from Dorstenia poinsettifolia, is described. Two routes starting from quercetin were explored, and 1 could be prepared if a prenyl group first was incorporated at C-6 of the protected quercetin followed by a condensation with citral at C-8. The key synthetic steps are a Mitsunobu reaction, an europium (III)-catalysed Claisen rearrangement coupled with cross-metathesis, and a benzopyran-forming geranylation. The two geranylated 3,5,3′,4′-tetrahydroxyflavonols prepared, 1 and 3, were assayed for antileishmanial activity against Leishmania amazonensis and Leishmania braziliensis, and found to be active. Compound 3 showed cytotoxic activity against leukaemia and lung cancer cells while 1 lacked cytotoxicity.     

An efficient stereoselective synthesis of (2S,4S,5R)-(−)- and (2R,4R,5S)-(+)-bulgecinine

A short synthetic route to (−)-and (+)-bulgecinine, the amino acid moiety of the bulgecins was achieved from the readily available nonchiral pool starting material cis-2-butene-1,4-diol in which a Claisen orthoester rearrangement and a Sharpless asymmetric dihydroxylation were used as the key steps.     

Facile Installation of 2‐Reverse Prenyl Functionality into Indoles by a Tandem N‐Alkylation–Aza‐Cope Rearrangement Reaction and Its Application in Synthesis

An unprecedented tandem N‐alkylation–ionic aza‐Cope (or Claisen) rearrangement–hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N‐alkylation and subsequent microwave‐irradiated ionic aza‐Cope rearrangement–hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2‐reverse quaternary‐centered prenylated indoles with high efficiency. Notably, unusual nonaromatic 3‐methylene‐2,3‐dihydro‐1H‐indole architectures, instead of aromatic indoles, are produced. Furthermore, the aza‐Cope rearrangement reaction proceeds highly regioselectively to give the quaternary‐centered reverse prenyl functionality, which often produces a mixture of two regioisomers by reported methods. The synthetic value of the resulting nonaromatic 3‐methylene‐2,3‐dihydro‐1H‐indole architectures has been demonstrated as versatile building blocks in the efficient synthesis of structurally diverse 2‐reverse prenylated indoles, such as indolines, indole‐fused sultams and lactams, and the natural product bruceolline D.     

Exocyclic vinyl ethers of ketofuranosides

Exocyclic vinyl ether derivatives of sugars are found in biosynthetic pathways and may serve as useful synthetic intermediates. The ketose subfamily of sugars is the least characterized in this field. Thus, the synthesis of exocyclic vinyl ether derivatives of ketohexoses via β-elimination was studied with respect to the nature of the 6-O leaving group and the protection of the 4-hydroxy group. We applied this study to protected l-sorbofuranoside and d-tagatofuranoside sugar derivatives in which the 4-hydroxy group and the 6-O-leaving group are in the syn configuration. Some reactions involving deprotection and reductive rearrangement of the tagatose-derived vinyl ether product were also studied.     

Asymmetric total synthesis of (2S,3S)-3-hydroxypipecolic acid

A synthetic route to (2S,3S)-3-hydroxypipecolic acid was achieved from readily available nonchiral pool starting material cis-2-butene-1,4-diol and involved Claisen orthoester rearrangement, Sharpless asymmetric dihydroxylation and intramolecular lactamisation of azido lactone as the key steps.     

Stereospecific rearrangement of α-hydroxyepoxide: efficient approach to the trans-bicyclo[9.3.0]tetradecane core en route to clavulactone

We document a synthetic route to trans-bicyclo[9.3.0]tetradecanes. The strategy is based on a quantitative and stereospecific Lewis acid mediated rearrangement of α-hydroxyepoxide to β-hydroxyketone, which paved the way for the synthesis of clavulactone and clavirolides.     

Synthesis and anti‐inflammatory effect of morachalcone B,morachalcone C,and analogs

An efficient method to synthesize morachalcones B and C ( 1 and 2 ) is described. Rap?Stoermer condensation and 1,3‐prenyl rearrangement were used as two key synthetic methods. Morachalcone C was obtained by photo‐oxygenation of morachalcone B. Morachalcones B and C showed moderate anti‐inflammatory activity.     

An efficient synthetic route to chiral 4-alkyl-1,2,3,4-tetrahydroquinolines: enantioselective synthesis of (R)-4-ethyl-1,2,3,4-tetrahydroquinoline

An efficient synthetic route to non-racemic chiral 4-alkyl-1,2,3,4-tetrahydroquinoline is described. (4R)-4-Ethyl-1,2,3,4-tetrahydroquinoline was obtained by the organoaluminum promoted modified Beckmann rearrangement involving the oxime sulfonate of (3R)-3-ethylindan-1-one. The required optically active indanone was obtained via an asymmetric conjugate reduction of (E)-ethyl 3-phenylpent-2-enoate.     

The first catalytic asymmetric total synthesis of ent-hyperforin

The first catalytic asymmetric total synthesis of ent-hyperforin was described here in detail. Keys to the success were a catalytic asymmetric Diels-Alder reaction, a stereoselective Clasien rearrangement, an intramolecular aldol cyclization, and a vinylogous Pummerer rearrangement. Along with the successful synthetic route, several attempted approaches toward the construction of bicyclo[3.3.1] core and the C2 oxidation were discussed.     

Synthesis and convenient functionalisation of pyridazinofurocoumarins: nitrogenated isosters of potent DNA inhibitors

Pyridazino[3,4-h]psoralens and pyridazino[3,4-j]angelicins are prepared in good yield from resorcinols through a direct, easy and generally applicable synthetic route. The key step in this route is the inverse electron-demand Diels-Alder reaction between linear or angular furocoumarins and 3,6-bis(methoxycarbonyl)-1,2,4,5-tetrazine to give the dicarboxymethylated tetracycles. The ester group in the peri position with respect to the oxygen in the furan ring can be regioselectively transformed to give primary or secondary amides. Similarly, the two ester groups in the tetracycle can be transformed in a high-efficiency process to give bis-amides that can be either symmetrical (from the same amine) or unsymmetrical (from two different amines).     

seco-Polycyclic polyprenylated acylphloroglucinols with unusual carbon skeletons from Hypericum ascyron

Three new seco-polycyclic polyprenylated acylphloroglucinols (PPAPs), ascyronones A–C (1–3), and a new biosynthetic precursor, ascyronone D (4), were isolated from Hypericum ascyron together with three known analogues (5–7). Compounds 1 and 2, sharing an unusual seven-membered carbon core fused with a γ-lactone ring, could be derived from 1,9-seco-PPAPs via further rearrangement. A biomimetic transformation from 5 to 1 was performed by using base-driven retro-Claisen and rearrangement cascade reaction, which further confirmed the structure of 1 and shed light to its possible biosynthetic pathway. Interestingly, all these compounds are decorated with a methyl group at C-5 instead of a prenyl or geranyl group in many other PPAPs. The isolates were evaluated for their inhibitory activities against five human tumor cell lines.     

Total synthesis of (±)-megistophylline I

(±)-Megistophylline I (1), carrying a dienone residue in the acridone framework, was synthesized using the Claisen rearrangement to introduce a prenyl group as a key step.     

Molecular diversity from aromatics. A tandem oxidative dearomatization,cycloaddition and reactivity modulation in excited states: synthesis of tricyclo[5.3.1.0]undecanes and bicyclo[4.2.0]octanes from common precursors

Stereoselective route to tricyclo[5.3.1.0^1,5]undecane and bicyclo[4.2.0]octane ring systems present in the molecular structure of tricycloillicinone, cedrenoids and endiandric acid, elysiapyrones, respectively, is described. A tandem oxidative dearomatization of o-hydroxymethylphenol, π⁴s+π²s cycloaddition, reactivity modulation in excited state and ring-closing metathesis are the key features of our approach.     

A new chiral 2-sulfonylamino-2′-phosphino-1,1′-binaphthyl ligand for highly enantioselective copper-catalyzed conjugate addition of diethylzinc to benzylideneacetones

A new axially chiral phosphine-sulfonamide ligand was prepared via a chiral component (R)-2-amino-2′-diphenylphosphinyl-1,1′-binaphthyl, which was conveniently synthesized through a new route involving hydrolysis of (R)-2-cyano-2′-phosphinyl-1,1′-binaphthyl followed by Hofmann rearrangement of the amide group. The new ligand was found to be very efficient in copper-catalyzed enantioselective conjugate addition of diethylzinc to acyclic enones such as benzylideneacetones, providing very high enantioselectivity up to 99% ee.     

Facial selectivity of the Ireland-Claisen rearrangement of allylic esters of 2-methyl and 2-methoxycyclopentanecarboxylic acids

Ketene silylacetals derived from prenyl and (Z)- and (E)-crotyl 2-methylcyclopentanecarboxylates (9) were subjected to the Ireland-Claisen rearrangement. All three substrates rearranged with complete facial selectivity, but the (Z)- and (E)-crotyl systems gave a mixture comprised of the same diastereomers of 1-(1-methyl-2-propenyl)-2-methylcyclopentanecarboxylic acid (14) in ratios of 2:1 and 1:2, respectively. In contrast, the ketene silylacetals prepared from allyl and prenyl 2-methoxycyclopentanecarboxylates (22) underwent rearrangements with both facial stereochemistries.     

Development of a scalable synthetic route towards a 2,2,6-trisubstituted chiral morpholine via stereoselective hydroalkoxylation

A scalable synthetic route towards a chiral 2,2,6-trisubstituted chiral morpholine, which is a known opioid antagonist, was developed. The synthetic route involves incorporating an aryl group via Suzuki-Miyaura coupling and stereoselective hydroalkoxylation catalyzed by trifluoromethanesulfonic acid. Late stage incorporation of both the aryl and N-alkyl groups make this route suitable for further SAR studies on this molecule.     

Prenyl carbamates: preparation and deprotection

Prenyloxycarbonylimidazole (PreocIm) and prenyl p-nitrophenyl carbonate (PreocOC₆H₄p-NO₂), two substitutes for the unstable prenyl chloroformate, allowed an efficient introduction of the prenyloxycarbonyl group to a variety of primary and secondary amines. Deprotection of prenyl carbamates was readily achieved by, first their conversion to 2-iodo-3-methoxy-3-methylbutyl carbamates with iodine in methanol followed by reductive β-elimination with zinc powder. These reaction conditions are compatible with the presence of a number of functional groups such as Boc and Cbz carbamates, sulfides, double bonds, indoles and aromatic ethers.     

An effective and convenient synthesis of cordycepin from adenosine

Cordycepin is a purine nucleoside analog with potent and diverse biological activities. Herein, we designed two methods to synthesize cordycepin. One method mainly converted the 3′-OH group into an iodide group and further dehalogenation to yield the final product. Although this method presented a short synthetic procedure, the synthesis had a low overall yield, resulting in only 13.5% overall yield. To improve the overall yield of cordycepin, another synthetic route was studied, which consisted of four individual steps: (1) 5′-OH protection (2) esterification (3) -O-tosyl (-OTs) group removal (4) deprotection. The key step in the synthetic method involved the conversion of 5′-O-triphenylmethyladenosine to 3′-O-tosyl-5′-O-triphenylmethyladenosine, using LiAlH₄ as reducing agent. The main advantages of this route were an acceptable total product yield and the commercial availability of all starting materials. The optimal reaction conditions for each step of the route were identified. The overall yield of cordycepin obtained from adenosine as the starting material was 36%.