Biological Evaluation of Isosteric Applicability of 1,3-Substituted Cuneanes as m-Substituted Benzenes Enabled by Selective Isomerization of 1,4-Substituted Cubanes.

We herein evaluate a biological applicability of 1,3-substituted cuneanes as an isostere of m-substituted benzenes based on its structural similarity. An investigation of a method to obtain 1,3-substituted cuneanes by selective isomerization of 1,4-substituted cubanes enables this attempt by giving a key synthetic step to obtain a cuneane analogs of pharmaceuticals having m-substituted benzene moiety. Biological evaluation of the synthesized analogs and in silico study of the obtained result revealed a potential usage of cuneane skeleton in medicinal chemistry.

Design, Synthesis, and Biological Evaluation of Water-Soluble Prodrugs of C5-Curcuminoid GO-Y030 Based on Reversible Thia-Michael Reaction.

Although curcumin and its analogs exhibit anticancer activity, they are still not used as anticancer drugs because of their water insolubility and extremely poor bioavailability. This study describes the development of water-soluble prodrugs of GO-Y030, a potent antitumor C5-curcuminoid, in an attempt to enhance its bioavailability. These prodrugs release the parent compound via a retro-thia-Michael reaction. To endow sufficient hydrophilicity onto GO-Y030 via a single thia-Michael reaction of an aqueous entity, we used a modified glycoconjugate with a thiol group. The water-solubilizing motif was installed on GO-Y030 by the thia-Michael reaction of propargyl-polyethylene glycol (PEG)-thiol and subsequent click chemistry (CuAAC) reaction with 1-glycosyl azide. Turbidity measurements revealed a significantly improved water solubility of the prodrugs, demonstrating that disaccharide conjugates were completely dissolved in water at 100 µM. Their cytotoxicity was comparable to that of the parent compound GO-Y030, indicating the gradual in situ release of GO-Y030. The release of GO-Y030 from GO-Y199 via the retro-thia-Michael reaction was demonstrated through a degradation study in water. Our retro-thia-Michael reaction-based prodrug system can be used for targeting cancer cells.

Asymmetric Total Synthesis of Cytotrienin A: Late-Stage Installation of C11 Side Chain onto the Macrolactam Scaffold.

Cytotrienin A, an ansamycin-class antibiotic, exhibits potent apoptosis-inducing activity and has attracted much attention as a lead compound for anticancer drugs. Herein, we report a new asymmetric synthetic route to cytotrienin A, employing an unexplored approach involving the late-stage installation of a C11 side chain onto the macrolactam core. In this strategy, we utilized the redox properties of hydroquinone and installed a side chain on the sterically hindered C11 hydroxy group by the traceless Staudinger reaction. This study also demonstrated that the boron-Wittig/iterative Suzuki-Miyaura cross-coupling sequence was effective for the concise and selective construction of the (E,E,E)-conjugated triene moiety. The developed route opens new opportunities for the structure-activity relationship studies of the side chains of these ansamycin antibiotics and the preparation of other synthetic analogs and chemical probes for further biological studies.

General Synthetic Approach to Diverse Taxane Cores.

Chemical synthesis of natural products is typically inspired by the structure and function of a target molecule. When both factors are of interest, such as in the case of taxane diterpenoids, a synthesis can both serve as a platform for synthetic strategy development and enable new biological exploration. Guided by this paradigm, we present here a unified enantiospecific approach to diverse taxane cores from the feedstock monoterpenoid (S)-carvone. Key to the success of our approach was the use of a skeletal remodeling strategy which began with the divergent reorganization and convergent coupling of two carvone-derived fragments, facilitated by Pd-catalyzed C-C bond cleavage tactics. This coupling was followed by additional restructuring using a Sm(II)-mediated rearrangement and a bioinspired, visible-light induced, transannular [2 + 2] photocycloaddition. Overall, this divergent monoterpenoid remodeling/convergent fragment coupling approach to complex diterpenoid synthesis provides access to structurally disparate taxane cores which have set the stage for the preparation of a wide range of taxanes.

Chromium-Salen Complex/Nitroxyl Radical Cooperative Catalysis: A Combination for Aerobic Intramolecular Dearomative Coupling of Phenols.

We describe an aerobic intramolecular dearomative coupling reaction of tethered phenols using a catalytic system consisting of a chromium-salen (Cr-salen) complex combined with a nitroxyl radical. This novel catalytic system enables formation of various spirocyclic dienone products including those unable to be accessed by previously reported methods efficiently under mild reaction conditions.

Toward the Creation of Induced Pluripotent Small (iPS) Molecules: Establishment of a Modular Synthetic Strategy for the Heronamide C-type Polyene Macrolactams and Their Conformational and Reactivity Analysis.

A highly modular synthetic strategy for the heronamide C-type polyene macrolactams was established by synthesizing 8-deoxyheronamide C (2). The developed strategy enabled not only the total synthesis of 8-deoxyheronamide C (2) but also the unified synthesis of four heronamide-like molecules named "heronamidoids" (5-8). Conformational and reactivity analysis of the heronamidoids clarified that (1) the C19 stereochemistry mainly affected the conformation of the amide linkage, resulting in the change of alignment of two polyene units and reactivity toward photochemical [6π + 6π] cycloaddition, and (2) the C8,C9-diol moiety is important for the conversion to the heronamide A-type skeleton from the heronamide C skeleton.

Design, Synthesis, and Antifungal Activity of 16,17-Dihydroheronamide C and ent-Heronamide C.

16,17-Dihydroheronamide C (8) and ent-heronamide C (ent-1) were designed as probes for the mode-of-action analysis of heronamide C (1). These molecules were synthesized by utilizing a highly modular strategy developed in the preceding paper. The evaluation of the antifungal activity of these compounds revealed the exceptional importance of the C16-C17 double bond for the antifungal activity of heronamide C and the existence of chiral recognition between heronamide C (1) and cell membrane components.

Expansion of Substrate Scope for Nitroxyl Radical/Copper-Catalyzed Aerobic Oxidation of Primary Alcohols: A Guideline for Catalyst Selection.

Four distinctive sets of optimum nitroxyl radical/copper salt/additive catalyst combinations have been identified for accommodating the aerobic oxidation of various types of primary alcohols to their corresponding aldehydes. Interestingly, less nucleophilic catalysts exhibited higher catalytic activities for the oxidation of particular primary allylic and propargylic alcohols to give α,ß-unsaturated aldehydes that function as competent Michael acceptors. The optimum conditions identified herein were successful in the oxidation of various types of primary alcohols, including unprotected amino alcohols and divalent-sulfur-containing alcohols in good-to-high yields. Moreover, N-protected alaninol, an inefficient substrate in the nitroxyl radical/copper-catalyzed aerobic oxidation, was oxidized in good yield. On the basis of the optimization results, a guideline for catalyst selection has been established.

Enantiospecific Entry to a Common Decalin Intermediate for the Syntheses of Highly Oxygenated Terpenoids.

Herein, we describe an enantiospecific route to one enantiomer of a common decalin core that is present in numerous highly oxygenated terpenoids. This intermediate is accessed in eight steps from (R)-carvone, an inexpensive, enantioenriched building block, which can be elaborated to the desired bicycle through sequential Fe(III)-catalyzed reductive olefin coupling and Dieckmann condensation. The same synthetic route may be applied to (S)-carvone to afford the enantiomer of this common intermediate for other applications.

Rearrangement of Hydroxylated Pinene Derivatives to Fenchone-Type Frameworks: Computational Evidence for Dynamically-Controlled Selectivity.

An acid-catalyzed Prins/semipinacol rearrangement cascade reaction of hydroxylated pinene derivatives that leads to tricyclic fenchone-type scaffolds in very high yields and diastereoselectivity has been developed. Quantum chemical analysis of the selectivity-determining step provides support for the existence of an extremely flat potential energy surface around the transition state structure. This transition state structure appears to be ambimodal, i.e., the fenchone-type tricyclic scaffolds are formed in preference to the competing formation of a bornyl (camphor-type) skeleton under dynamic control via a post-transition state bifurcation (PTSB).

Catalytic Oxygenative Allylic Transposition of Alkenes into Enones with an Azaadamantane-Type Oxoammonium Salt Catalyst.

The first catalytic oxygenative allylic transposition of unactivated alkenes into enones has been developed using an oxoammonium salt as the catalyst. This reaction converts various tri- and trans-disubstituted alkenes into their corresponding enones with transposition of their double bonds at ambient temperature in good yields. The use of a less-hindered azaadamantane-type oxoammonium salt as the catalyst and a combination of two distinct stoichiometric oxidants, namely, iodobenzene diacetate and magnesium monoperoxyphthalate hexahydrate (MMPP⋅6 H2 O) are essential to facilitate the enone formation efficiently.

Synthesis of 1,3-Cycloalkadienes from Cycloalkenes: Unprecedented Reactivity of Oxoammonium Salts.

Few methods allow for the direct conversion of cycloalkenes into cycloalkadienes with high chemo- and regioselectivity. Herein, we report a convenient one-pot process for this transformation that involves the unprecedented N-preferential group transfer of N-oxoammonium salts to cycloalkenes, followed by Cope elimination, to afford cycloalkadienes at room temperature and pressure.

Mechanistic insight into aerobic alcohol oxidation using NOx-nitroxide catalysis based on catalyst structure-activity relationships.

The mechanism of an NOx-assisted, nitroxide(nitroxyl radical)-catalyzed aerobic oxidation of alcohols was investigated using a set of sterically and electronically modified nitroxides (i.e., TEMPO, AZADO (1), 5-F-AZADO (2), 5,7-DiF-AZADO (3), 5-MeO-AZADO (4), 5,7-DiMeO-AZADO (5), oxa-AZADO (6), TsN-AZADO (7), and DiAZADO (8)). The motivation for the present study stemmed from our previous observation that the introduction of an F atom at a remote position from the nitroxyl radical moiety on the azaadamantane nucleus effectively enhanced the catalytic activity under typical NOx-mediated aerobic-oxidation conditions. The kinetic profiles of the azaadamantane-N-oxyl-[AZADO (1)-, 5-F-AZADO (2)-, and 5,7-DiF-AZADO (3)]-catalyzed aerobic oxidations were closely investigated, revealing that AZADO (1) showed a high initial reaction rate compared to 5-F-AZADO (2) and 5,7-DiF-AZADO (3); however, AZADO-catalyzed oxidation exhibited a marked slowdown, resulting in ∼90% conversion, whereas 5-F-AZADO-catalyzed oxidation smoothly reached completion without a marked slowdown. The reasons for the marked slowdown and the role of the fluoro group are discussed. Oxa-AZADO (6), TsN-AZADO (7), and DiAZADO (8) were designed and synthesized to confirm their comparable catalytic efficiency to that of 5-F-AZADO (2), providing supporting evidence for the electronic effect on the catalytic efficiency of the heteroatoms under NOx-assisted aerobic-oxidation conditions.

Highly chemoselective aerobic oxidation of amino alcohols into amino carbonyl compounds.

The direct oxidation of unprotected amino alcohols to their corresponding amino carbonyl compounds has often posed serious challenges in organic synthesis and has constrained chemists to adopting an indirect route, such as a protection/deprotection strategy, to attain their goal. Described herein is a highly chemoselective aerobic oxidation of unprotected amino alcohols to their amino carbonyl compounds in which 2-azaadamantane N-oxyl (AZADO)/copper catalysis is used. The catalytic system developed leads to the alcohol-selective oxidation of various unprotected amino alcohols, carrying a primary, secondary, or tertiary amino group, in good to high yield at ambient temperature with exposure to air, thus offering flexibility in the synthesis of nitrogen-containing compounds.

C-H Alkylation of Cubanes via Catalytic Generation of Cubyl Radicals.

A catalytic method for the C-H alkylation of cubanes is described. Some hydrogen atom transfer catalysts enable the direct abstraction of a hydrogen atom from the C-H bond of cubanes, followed by conjugate addition of the generated cubyl radicals to electron-deficient alkenes. Synthetic applications of the functionalization method developed are also described.

Controlled Aerobic Oxidative Dimerization of Hydroxystilbenoids by Chromium Catalysis.

Aerobic oxidative dimerization of hydroxystilbenoids is described. A Cr-salen complex catalyzed the dimerization of hydroxystilbenoids in 1,1,1,3,3,3-hexafluoroisopropanol to form compounds comprising a natural product-like scaffold (quadrangularin) or its precursor depending on the aromatic substituents. The addition of a catalytic amount of scandium triflate [Sc(OTf)3] to the reaction system altered the reaction outcome to give a different natural product-like compound, a pallidol-type dimer.

Sequential click modification of a lithium-ion endohedral fullerene connecting small molecules through a dieneazide linker.

A versatile method for the chemical modification of a lithium-ion endohedral fullerene (Li+@C60) to connect various small molecules is described. The designed dieneazide linker enables the facile connection of Li+@C60 with small molecules bearing a terminal alkyne via Huisgen annulation and a subsequent Diels-Alder reaction. This strategy significantly expands the diversity of small molecules to be attached by Li+@C60.

Enantiocontrolled Access to an Intermediate for Highly Functionalized Clovane-Type Terpenoids: Formal Synthesis of Rumphellclovane E.

We describe an enantiocontrolled route to a versatile intermediate for the synthesis of highly functionalized clovane-type terpenoids. The synthetic route commenced with (R)-carvone, a commercially available and enantioenriched building block, and an oxygenative strategy was used to concisely access a clovane scaffold. One example of the versatility of the obtained intermediate was the formal synthesis of rumphellclovane E.

9-Azanoradamantane N-oxyl (Nor-AZADO): a highly active organocatalyst for alcohol oxidation.

A highly active organocatalyst for alcohol oxidation has been developed. 9-Azanoradamantane N-oxyl (Nor-AZADO 4), constituting an unhindered, stable nitroxyl radical, exhibits superior catalytic activity to 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and AZADOs in the oxidation of alcohols to their corresponding carbonyl compounds.

ortho-C-H Acetoxylation of Cubane Enabling Access to Cubane Analogues of Pharmaceutically Relevant Scaffolds.

A novel method of introducing an oxygen functionality into a cubane core was developed using a transition-metal-catalyzed directed acetoxylation methodology via C-H activation. The obtained compounds were derivatized into cubane analogues of pharmaceutically relevant structural motifs, namely, acetylsalicylic acid and coumarin motifs, which could potentially act as bioisosteres of these scaffolds.