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This paper describes the total syntheses of spirooliganones A and B, which provides control over the stereochemistry of the spiro center via a cascade reaction involving the in situ formation of an o-quinone methide and a hetero-Diels–Alder reaction.

We report herein the first total synthesis of saptomycin H (

Reported herein is a de novo synthesis of a dimerization-ready flavan unit via the Pummerer/Friedel–Crafts cascade, enabling facile access to oligomeric proanthocyanidins.

We report the enantioselective total syntheses of preussomerins EG

This Account showcases three diastereotopos-selective reactions exploited in our complex natural syntheses.1 Introduction2 Malyngolide: Hydroalumination of Bisalkynyl tert-Alcohols3 Cavicularin: Acetal Cleavage4 Carthamin: Bromoacetoxylation5 Conclusions

We report an improved synthesis of a C-Glycosyl quinochalcone that is a key intermediate in our total synthesis of carthamin, a natural red pigment of traditional heritage. The C-glycosyl quinochalcone is prepared by regioselective de-O-methylation of a C-glycosyl bromodienone, and installation of a p-coumaroyl side chain through an O→C acyl rearrangement.

In connection with our synthetic study toward the dimeric pyranonaphthoquinone antibiotics, actinorhodin (1) and β-naphthocyclinone (3), we describe herein the synthesis of a monomer, hemi-actinorh...

The first total synthesis of parameritannin A2 (1), a branched epicatechin (EC) tetramer is reported. The "phloroglucinol trick" was used to circumvent two synthetic issues encountered when assembling four EC units, namely, the steric constraint and the formation of the C4-C6 interflavan linkage. As a substructure of the middle EC unit, phloroglucinol enabled the single-step assembly of two EC units (top and side) through A-type linkages. The middle EC unit was constructed by conducting a newly developed three-carbon flavan annulation via a Pummerer/Friedel-Crafts cascade reaction to furnish a trimeric intermediate bearing a thio-leaving group at C4 position, which allowed the final installation of the bottom EC unit.

Toward a total synthesis of acremoxanthone A, we report a model study on the construction of the EFG ring system. The key steps include (1) an intermolecular 1,3-dipolar cycloaddition of an aryl nitrile oxide with a dienone, and (2) an SNAr reaction for construction of the F ring.

Substrate scope of the thiolate-mediated reductive cyclization of keto-enones was studied, revealing the applicability and novel mechanistic insights.

Toward a stereoselective total synthesis of the lactonamycins, we recently reported an approach to the DEF-ring system. Here we report a model study for constructing the ABCD-ring system, revealing a viable approach through (1) construction of the C-ring by asymmetric benzoin cyclization, (2) introduction of an angular hydroxy group through oxidation of an isoxazolium salt, and (3) construction of the AB rings through a ring-opening/closing sequence.

An intramolecular benzyne-phenolate [4+2] cycloaddition is reported. Benzyne precursors, having vicinal halogen-sulfonate functionalities, linked with a phenol(ate) by various tether groups undergo efficient intramolecular [4+2] cycloaddition by treatment with either Ph3 MgLi or nBuLi for halogen-metal exchange to form various benzobarrelenes.

The number of people worldwide suffering from Alzheimer’s disease (AD) and type 2 diabetes (T2D) is on the rise. Amyloid polypeptides are thought to be associated with the onset of both diseases. Amyloid-β (Aβ) that aggregates in the brain and human islet amyloid polypeptide (hIAPP) that aggregates in the pancreas are considered cytotoxic and the cause of the development of AD and T2D, respectively. Thus, inhibiting amyloid polypeptide aggregation and disaggregation existing amyloid aggregates are promising approaches in the therapy and prevention against both diseases. Therefore, in this research, we evaluated the Aβ/hIAPP anti-aggregation and disaggregation activities of A-type procyanidins 1–7 and their substructures 8 and 9, by conducting structure–activity relationship studies and identified the active site. The thioflavin-T (Th-T) assay, which quantifies the degree of aggregation of amyloid polypeptides based on fluorescence intensity, and transmission electron microscopy (TEM), employed to directly observe amyloid polypeptides, were used to evaluate the activity. The results showed that catechol-containing compounds 1–6 exhibited Aβ/hIAPP anti-aggregation and disaggregation activities, while compound 7, without catechol, showed no activity. This suggests that the presence of catechol is important for both activities. Daily intake of foods containing A-type procyanidins may be effective in the prevention and treatment of both diseases.

We report the stereocontrolled synthesis of enantiopure

Flavan-derived polyphenols are widely distributed in the plant kingdom, and have long been known to possess remarkable biological activity and a positive effect on human health. However, the detailed biochemical functions of this class of molecules at a molecular level are still not well studied due to the limited availability of natural samples in sufficient quantity and quality. This account gives an overview of our synthetic efforts towards this class of molecules which exploit selective functionalization of the C(4) position of the flavan skeleton. Various nucleophilic components could be introduced into this position via SN1-type substitution. As part of our synthetic studies on flavan oligomers, an orthogonal activation method that employs two distinct flavan units was developed. This enabled iterative coupling to give linear and/or doubly-linked flavan oligomers to be achieved.

Photoirraditation of substituted 1,2-naphthoquinones gives the corresponding oxacycle via intramolecular redox reaction, which enabled net CH functionalization of the proximal position to the excited carbonyl group of the quinones. The substrate scope and mechanistic insights are described.

A model study for the enantioselective total synthesis of γ-rubromycin has revealed a promising approach for constructing the chiral, nonracemic bicyclic spiroacetal via the stereospecific photoredox reaction of 1,2-naphthoquinone ether.

The first total synthesis of selligueain A (4), a plant-derived sweet polyphenol, has been achieved. The key step was the de novo synthetic approach to the selectively protected epiafzelechin unit 10, which was divergently converted to three flavan units 7, 8, and 9. These components were combined by an orthogonal activation and annulation method, enabling assembly of the characteristic trimeric structure with single and double interflavan linkages.

The first total synthesis of oxirapentyn D from myo-inositol has been achieved by utilizing chelation-directed bridgehead lithiation of a hydrazone derivative.

We report herein the asymmetric total synthesis of (+)-engelharquinone and its epoxide by exploiting two key reactions; (1) Rhodium catalyzed asymmetric 1,4-addition and (2) thiolate-mediated reduc...

Intramolecular photoredox reactions of naphthoquinone derivatives were found to proceed in a stereospecific manner. This method was used as a basis for the enantioselective total synthesis of (-)-spiroxin C.

Toward the total synthesis of carthamin, a stereoselective approach to the C-glycosyl quinochalcone intermediate is reported via the desymmetrization of a pseudo-Cs-symmetric C-glycosyl cyclohexadienone.

The total syntheses of (-)-rotenone and (-)-dalpanol have been achieved by a group-selective, stereospecific 1,2-shift of an epoxy alcohol and SN Ar cyclizations. Three oxacycles are constructed, thus illustrating a versatile synthetic route to various rotenoids.

Herein, a two-step procedure for the preparation of oxygenated

Herein, a two-step procedure for the preparation of oxygenated ortho-methylbenzaldehyde derivatives, starting from commercially available bromoarenes, is described. The synthesis features the simultaneous and highly regioselective installation of both the methyl and the formyl group onto the benzene core via benzyne [2+2] cycloadditions with acetaldehyde lithium enolate to give the corresponding benzocyclobutenols in high yields. Bond-selective ring opening of the benzocyclobutenols under basic conditions in methanol delivers the title compounds.

We report the first total synthesis of the proposed structure of ardimerin, which was achieved in 14 steps starting from 2,3,4-trimethoxybenzoic acid. The key steps include the β-selective formation of the crucial C-glycoside linkage and stepwise construction of the strained 8-membered salicylide core. The synthesis revealed that the proposed structure 1 does not match the natural product. A proposal is made for reassigning the isolated natural product to the already known structure of bergenin. Interesting properties of the synthetic 8-membered salicylides are documented, including their susceptibility toward nucleophilic ring opening and the bowl chirality. This article is protected by copyright. All rights reserved.

Synthetic study on carthamin, a natural red pigment, is described. Attempts at the construction of the key quinol C-glycoside structure by oxidative dearomatization of C-glycosyl phenols were hampered by the competing cleavage of the C1–C2 bond in the sugar moiety. By employing the 2-O-acetyl protection, the projected reaction proceeded smoothly, giving the desired products in good to excellent yields. An interesting photochemical stability/instability of the chalcone geometry in the synthetic compounds was observed.

Stereodefined α-iodovinyl sulfoxides bearing a sulfinyl group and an iodo group were prepared by a one-pot iodination/Horner–Wadsworth–Emmons reaction protocol. This reaction can be applied to a wide range of aldehydes, and further application was demonstrated.

Described herein is a flexible modular approach to planar chiral carba-paracyclophanes via the stepwise assembly of two distinct side arms and the aromatic core followed by ring-closing olefin metathesis. Planar chirality is induced by one chiral sulfinyl group by forming a hydrogen bond to the phenol in the aromatic unit.

The total syntheses of pusilatins A (2), B (3), and C (5), macrocyclic bisbibenzyl dimers isolated from Japanese liverwort are reported. The common monomeric unit (6) was prepared via macrocyclization of an o-sulfinylfluorobenzene derivative by SNAr attack of an internal phenol, which was exploited for site-selective dimerizations en route to 2, 3, and 5.

The bis-C-glucosyl flavonoid vicenin-2 has been synthesized by exploiting bis-C-glycosylation of 1,3,5-trifluorobenzene and arom. nucleophilic substitution to transform fluorine atoms to oxygen functions in excellent yield. [on SciFinder(R)]

The first enantioselective total syntheses of engelharquinone (2) and its epoxide 3 have been achieved. The key steps include (1) catalytic asymmetric 1,4-addition of a naphthylboronic acid derivative to a masked naphthoquinone derivative by using a chiral Rh-complex and (2) thiolate-promoted stereospecific construction of the bicyclo[3.2.1]octadienone scaffold.

The first stereoselective syntheses of doubly linked (A-type) oligocatechins, (+)-procyanidin A2 and (+)-cinnamtannin B1, have been achieved. Ethylenedioxy-bridged flavans served as excellent platforms, thus allowing annulation with nucleophilic catechin units in a stereoselective manner. An additional key was the new synthetic approach to selectively protected nucleophilic catechin, thus enabling regioselective construction of the key dioxabicyclo skeleton of the A-type oligocatechins.

The total syntheses of (-)-rotenone and (-)-dalpanol have been achieved by a group-selective, stereospecific 1,2-shift of an epoxy alcohol and S

Goupiolone A, a benzotropolone natural product, has been synthesized by assembling a benzocyclobutene derivative and a silyl-substituted cyclopropane unit, followed by thermal ring enlargement. The synthetic sample did not correspond to the reported data. On the basis of biogenetic considerations, an alternative structure with a catechol moiety was proposed, and the synthesis established it as the correct structure.

Reaction of bisenone (I) under conditions A) produces the desired skeleton (III) via the active intermediate (II).

Flavan-derived polyphenols (catechin derivatives), widely destributed in the plant kingdom, have been given much considerable attention owing to their significant bioactivitites coupled with their extreme structural diversity. However, biochemical functions of this class of molecules are still not well understood because of the limited availavility of natural samples in sufficient quantity and quality. Here we report our synthetic challenges toward flavan-derived polyphenols, based on the flavonoid-sugar analogy. The key for success was the C(4)-elaboration of the flavan skeleton, which posed an important relevance to their structure diversification both in terms of the biogenetic origin of flavan derivatives as well as chemical synthesis of this class of compounds. Various nucleophilic units could be introduced to the C(4) position via the SN1-type substitution, and orthogonal activation of two distinct flavan units enabled block assembly of linear catechin oligomers. These methodologies would serve as a reliable way to supply valuable, homogeneuous samples for biological testing. DOI 10.1002/tcr.201100026

A viable route has been developed for the selective synthesis of the 4→6-linked catechin dimers, scarcely accessible from Nature and/or through synthesis. An acyclic nucleophilic catechin precursor (seco-catechin) was used for the regioselective union with an electrophilic catechin unit, and subsequent pyran cyclization gave the desired 4→6-linked dimers, i.e., procyanidin B6 and catechin-(4α→6)-gallocatechin.

A general synthetic route to the epi-series catechins was developed based on the reverse polarity strategy. Aromatic nucleophilic substitution reaction followed by the sulfinyl-metal exchange and cyclization enabled stereo-controlled access to various members of epi-series catechins and their 3-gallates.