Total synthesis of indoline alkaloids: A cyclopropanation strategy

Indoline alkaloids constitute a large class of natural products; their diverse and complex structures contribute to potent biological activities in a range of molecules. Designing an appropriate strategy for the total synthesis of indoline alkaloids is a difficult task that depends on being able to efficiently assemble the core architectures. The best strategies allow access to a variety of different indoline alkaloid structures in a minimum of steps. The cyclopropanation of simple olefins and the subsequent synthetic transformation of the resulting cyclopropyl intermediates has been intensively studied in recent decades. In contrast, the cyclopropanation of enamines, especially for the construction of complex nitrogen-containing ring systems, remained relatively unexplored. Previous success with the cyclopropanation of simple indoles to form stable indolylcyclopropanocarboxylates encouraged us to explore the assembly of indoline alkaloid skeletons with cyclopropanation as a key reaction. Theoretically, indolylcyclopropanocarboxylates are doubly activated by a vicinally substituted amino group and carboxyl group; that is, they are typical donor-acceptor cyclopropanes. Accordingly, they tend to yield an active iminium intermediate, which can undergo inter- and intramolecular nucleophilic reactions to form the core structure of indoline alkaloids with an expanded ring system. In this Account, we summarize our efforts to develop a cascade or stepwise reaction of cyclopropanation/ring-opening/iminium cyclization (the CRI reaction) on tryptamine derivatives for assembling indoline alkaloid skeletons. With the CRI approach, three types of indoline alkaloid skeletons have been efficiently constructed: (i) hexahydropyrrolo[2,3-b]indoline (type I), (ii) tetrahydro-9a,4a-iminoethano-9H-carbazole (type II), and (iii) tetrahydroquinolino[2,3-b]indoline (type III). The effects of substituents on tryptamine derivatives were carefully investigated for inter- and intramolecular CRI reactions during construction of type I and type II skeletons. These results provided a basis for the further design and synthesis of complex natural products containing nitrogen. The usefulness of the CRI reaction is well demonstrated by our total synthesis of structurally intriguing indoline alkaloids such as N-acetylardeemin, minfiensine, vincorine, and communesin F. In addition, we highlight advances by other groups in construction of the three types of skeletons as well as their total syntheses of these indoline alkaloids. Discussion of the total syntheses of these indoline alkaloids focuses on comparing the individual synthetic strategies for forming the ring systems embedded in the final products. We also describe the total synthesis of perophoramidine, which has the same type III skeleton as communesin F. The observation of a retro Diels-Alder reaction during our synthesis of communesin F inspired the hetero Diels-Alder reaction on which our total synthesis of perophoramidine was based.     

Masked o-benzoquinones in organic synthesis

An account of the synthetic utility of masked o-benzoquinones is provided. The inter- and intramolecular Diels-Alder reactions of in situ generated masked o-benzoquinones produced cycloadducts in excellent selectivities. New synthetic methodologies have been developed for the synthesis of highly substituted ring systems including bicyclo[2.2.2]octenones, oxatricycles, triquinanes, polysubstituted cyclohexanes, and bicyclo[4.2.2]decenones with complete stereocontrol from easily accessible 2-methoxyphenols via the Diels-Alder reaction of masked o-benzoquinones. Other reactions of adducts derived from masked o-benzoquinones are also described. The efficacy of our methodology is demonstrated by several examples of the total synthesis of natural products.     

Aminocatalytic Asymmetric Diels-Alder Reactions via HOMO Activation

In the first successful catalytic asymmetric Diels-Alder reaction in 1979, Koga and colleagues used a chiral aluminum complex as a Lewis acid catalyst, but since then, researchers have developed numerous catalytic systems for these reactions. By 2000, several chiral organic compounds, such as the salts of imidazolidinones or TADDOLs, emerged as robust catalysts in the asymmetric Diels-Alder reactions. According to frontier molecular orbital theory, most of these catalysts employ a LUMO-lowering strategy as a means of activating electron-deficient dienophiles. Only rarely do chiral catalysts take advantage of the alternative strategy of activating the HOMO. In this Account we will discuss the development of asymmetric Diels-Alder reactions based on the HOMO-raising effects of chiral amines. First, we show that enamine intermediates formed in situ between an amine catalyst and enolizable aliphatic aldehydes can act as electron-rich dienophiles in inverse-electron-demand Diels-Alder reactions. We describe the preparation of a variety of oxygen- or nitrogen-containing heterocycles with high optical purity. Then, we demonstrate that the dienamine species from α,β-unsaturated aldehydes can act either as electron-rich dienes in normal-electron-demand Diels-Alder reactions or as dienophiles in inverse-electron-demand Diels-Alder reactions. These reactions generally occur with high chemo-, regio-, and stereoselectivity. Finally, we introduce a new activation mode for Diels-Alder reactions, in which reactive trienamine intermediates derived from 2,4-dienals or even 2,4-dienones play a key role. Notably, we observe remarkable β,ε-regioselectivity and obtain excellent stereocontrol even at the very remote ε-reactive center-up to seven bonds away from the chiral center of the amine catalyst. These results demonstrate that a HOMO-activation strategy via aminocatalysis could become a significant tool in asymmetric Diels-Alder reactions. In addition, these reactions using enamine, dienamine, or trienamine intermediates produce a diverse array of densely functionalized cyclic scaffolds, which may serve as valuable structures in drug discovery and natural product synthesis.     

Sultones in Organic Synthesis

Sultones are readily prepared by intramolecular Diels–Alder reaction of vinylsulfonates in an often highly stereoselective fashion. Various methods for the synthetic elaboration of these heterocycles have been developed and applied to the total synthesis of biologically active natural products.     

A New Method for the Stereoselective Synthesis of Nucleosides by Means of Sodium Borohydride Mediated Reductive C-C or C-N Bond Cleavage Reaction

New dienophiles, dimethyl acetoxymethylenemalonate and its analogues, have been synthesized. These dienophiles reacted with cyclopentadiene to give Diels-Alder adducts, which served as versatile synthetic precursors for carbocyclic C-nucleosides. The method has the following three characteristics: (1) the C-C bond in the adduct originated from the dienophile can be cleaved stereoselectively by the reductive retrograde aldol (RRA) reaction, (2) the CC bond in the adduct serves as a latent functionality of 2′- and 3′- positions of the nucleoside, and (3) the malonate unit can be transformed to a variety of heterocycles. The high pressure mediated Diels-Alder reaction of furan with the same dienophiles also gave the cycloadducts, which served as synthons for C-nucleosides. Use of chiral dienophiles, such as di-1-menthyl acetoxymethylenemalonate, for the above Diels-Alder reactions has offered a new route to the enantioselective synthesis of C-nucleosides and their carbocyclic analogues. Essentially the same methodology has also been applied to the synthesis of carbocyclic nucleosides from 2-azabicyclo[2.2.1]hept-5-en-3-one, in which a reductive amido bond cleavage reaction similar to (1) is involved. Synthesis of carbocyclic oxetanocin and its analogues is also described.     

Total Synthesis and Structural Elucidation of Two Unusual Non-Methylene-Interrupted Fatty Acids in Ovaries of the Limpet <Emphasis Type="Italic">Cellana toreuma</Emphasis>

In our previous study, unusual odd‐numbered dienoic acids with a terminal olefin were found as minor components in ovaries of the Japanese limpet Cellana toreuma, and the synthetic interests have been focused onto their structural confirmation and the inspection into their potential biological activity. Here, we describe an efficient and stereoselective total synthesis of two new unusual dienoic acids, 19:2?7,18 and 21:2?7,20, through a common pathway involving the strategic combination of alkyne‐zipper reaction and Lindlar hydrogenation for the construction of their unique carbon chains. In our synthetic study, 2‐propyn‐1‐ol was at first subjected to alkylation and alkyne‐zipper reaction to form the two fragments, and the subsequent carbon chain elongation was achieved by the usual coupling reaction to obtain the C‐19 and C‐21 products bearing an internal acetylenic group. Then, the internal acetylenic group of these products was subjected to Lindlar hydrogenation to form a Z‐alkenyl moiety, and the subsequent deprotection of the products was carried out under an acidic condition without isomerization of the internal Z‐alkenyl group. Total synthesis of target fatty acids, 19:2?7,18 and 21:2?7,20, was finally accomplished by two‐step oxidation of the resulting alcohols into carboxylic acids in a highly chemoselective manner, and the structures of these unusual natural fatty acids were finally elucidated by identifying the GC–MS spectra of the methyl esters of authentic and synthetic fatty acids.     

The Development of Alkoxide-Directed Metallacycle-Mediated Annulative Cross-Coupling Chemistry

Alkoxide-directed metallacycle-mediated cross-coupling is a rapidly growing area of reaction methodology in organic chemistry. Over the last decade, developments have resulted in more than thirty new and highly selective intermolecular (or “convergent”) C−C bond-forming reactions that have established powerful retrosynthetic relationships in stereoselective synthesis. While early studies were focused on developing transformations that forge a single C−C bond by way of a functionalized and unsaturated metallacyclopentane intermediate, recent advances mark the ability to employ this organometallic intermediate in additional stereoselective transformations. Among these more advanced coupling processes, those that embrace the metallacycle in subsequent [4+2] chemistry have resulted in the realization of a number of highly selective annulative cross-coupling reactions that deliver densely functionalized and angularly substituted carbocycles. This review discusses the early development of this chemistry, recent advances in reaction methodology, and shares a glimpse of the power of these processes in natural product synthesis.     

A Biomimetic Approach to Taxol: Stereoselective Synthesis of a 12-Membered Ring Ene-Epoxide

The stereoselective synthesis of a taxol intermediate via a biomimetic route is described. Aldol condensation of γ-butyrolactone and citral derivatives generated three stereogenic centers at positions C1, C2, and C11 corresponding to taxol. Intramolecular alkylation of the cyanohydrin ether efficiently formed the 12-membered ring system in which stereoselective reduction, followed by directed epoxidation, afforded the key intermediate epoxide.     

Asymmetric Synthesis of Polyfunctionalized Mono‐, Bi‐, and Tricyclic Carbon Frameworks via Organocatalytic Domino Reactions

An asymmetric organocatalytic multi‐component domino reaction is used as a key process for the stereoselective synthesis of polysubstituted mono‐ and bicyclic cyclohexene‐carbaldehydes. Furthermore, the extension of the domino reaction and further synthetic transformations of the cascade products were investigated. The combination of the three‐step cascade with an intramolecular Diels–Alder reaction opens up an entry to tricyclic decahydroacenaphthylene and decahydrophenalene skeletons, which are valuable characteristic carbon cores of natural products.     

Alkaloid Synthesis via Gold-Catalyzed Carbon-Carbon Bond Formation Using Enamine-type Nucleophile

In this account, various types of cyclizations/cycloisomerizations of alkyne substrates with internal enamine-type nucleophiles including enamide, enaminone, enaminoester and in situ generated enamine in the presence of electrophilc transition metal catalysts (Pt, Rh, Cu, Au) are firstly introduced. Then, the applications of the gold-catalyzed reactions in the synthesis of an array of alkaloids are discussed. These natural products feature heterocyclic structural motifs such as pyridine, azaanthraquinone, pyridoacridine, pyrrole, indole, indolenine and carbazole, as well as chiral tetrahydroindolizine, azocine units and six-membered carbocycles bearing a quaternary carbon center.     

Design and Synthesis of Chiral Zn2+ Complexes Mimicking Natural Aldolases for Catalytic C–C Bond Forming Reactions in Aqueous Solution

Extending carbon frameworks via a series of C–C bond forming reactions is essential for the synthesis of natural products, pharmaceutically active compounds, active agrochemical ingredients, and a variety of functional materials. The application of stereoselective C–C bond forming reactions to the one-pot synthesis of biorelevant compounds is now emerging as a challenging and powerful strategy for improving the efficiency of a chemical reaction, in which some of the reactants are subjected to successive chemical reactions in just one reactor. However, organic reactions are generally conducted in organic solvents, as many organic molecules, reagents, and intermediates are not stable or soluble in water. In contrast, enzymatic reactions in living systems proceed in aqueous solvents, as most of enzymes generally function only within a narrow range of temperature and pH and are not so stable in less polar organic environments, which makes it difficult to conduct chemoenzymatic reactions in organic solvents. In this review, we describe the design and synthesis of chiral metal complexes with Zn²⁺ ions as a catalytic factor that mimic aldolases in stereoselective C–C bond forming reactions, especially for enantioselective aldol reactions. Their application to chemoenzymatic reactions in aqueous solution is also presented.     

Strategy Evolution in the Total Synthesis of Spirastrellolide A Methyl Ester

This review highlights the many challenges overcome during our recent synthetic campaign towards spirastrellolide A, a structurally unprecedented antimitotic marine macrolide that potently and selectively inhibits protein phosphatases, and represents a promising lead for anticancer drug discovery. Faced with the initial stereochemical ambiguities, a flexible and modular synthetic strategy was adopted for the construction of increasingly elaborate fragments of the architecturally complex macrolactone to enable further structural elucidation by detailed NMR analysis. A reliable and convergent synthetic route evolved to encompass the use of boron-mediated aldol reactions to install much of the required oxygenation pattern and associated stereocenters, together with a tandem double Sharpless asymmetric dihydroxylation and cyclization to efficiently access the signature DEF-[5,6,6]-bis-spiroacetal region from a linear diene precursor. A pivotal sp²-sp³ Suzuki fragment coupling, followed by a double hydroboration of the resulting diene, then provided an advanced C17-C40 aldehyde which was coupled with a suitable C1-C16 alkyne. Following BC-spiroacetalization, a high yielding Yamaguchi macrolactonization afforded the C1-C40 macrocyclic core, where the full side chain was then introduced by sequential olefin cross-metathesis and π-allyl Stille cross-coupling, culminating in the first total synthesis of spirastrellolide A methyl ester.     

Stereoselective construction of quaternary carbon stereocenters via a semipinacol rearrangement strategy

Quaternary carbon stereocenters are found in a broad range of organic compounds, including important bioactive natural products and medicinal agents. Given their ubiquity and the significant synthetic challenges they present, quaternary carbon stereocenters have long attracted great interest from synthetic organic chemists. Numerous efforts have been devoted to their construction, leading to a spectrum of strategies for creating stereogenic quaternary carbon centers. In this context, the semipinacol rearrangement has proven successful. In this extension of the pinacol rearrangement, the 1,2-carbon-to-carbon migration in a 1,2-diol has been expanded to include leaving groups other than the hydroxyl group. Over the past decade, our laboratory has explored the semipinacol rearrangement strategy for the stereoselective construction of quaternary carbon stereocenters. We have investigated various substrates, including 2,3-epoxy alcohols (also termed α-hydroxy epoxides), 2,3-aziridino alcohols, and allylic alcohols. Several promoters that effect the semipinacol rearrangement have been identified, including Lewis acids based on Al, Sm, B, Zn, and Ti for the rearrangement of α-hydroxy epoxides and 2,3-aziridino alcohols; cationic halogen species for the rearrangement of allylic alcohols; and cinchona alkaloids and chiral phosphoric acid for the asymmetric semipinacol rearrangement. Our research efforts have led to a series of valuable synthetic methods, including (1) a tandem semipinacol rearrangement and Meerwein-Ponndorf-Verley reduction, (2) a tandem semipinacol rearrangement and Tishchenko reaction, (3) a tandem semipinacol rearrangement with either an allylation or a propargylation, (4) a tandem semipinacol rearrangement and Schmidt reaction, (5) a semipinacol rearrangement of 2,3-aziridino alcohols, (6) a semipinacol rearrangement of allylic alcohols induced by halogen cation, (7) a tandem aziridination and semipinacol rearrangement of allylic alcohols, and (8) asymmetric semipinacol rearrangements with chiral organic catalysts. One hallmark of these reactions is the creation of stereogenic quaternary carbon centers with high levels of stereocontrol. In this Account, we describe the development of these synthetically useful methodologies and their successful application to the total syntheses of natural products. Our results demonstrate that the semipinacol rearrangement of carefully designed substrates constitutes an efficient approach to the stereoselective construction of quaternary carbon centers. These reactions have produced a broad array of useful compounds that lend themselves to further elaboration. Furthermore, the total synthesis of a series of alkaloids, with significant bioactivity and intriguing molecular architecture, was achieved through these semipinacol rearrangement strategies, highlighting their synthetic value.     

Stereoselective total synthesis of axially chiral natural products via biaryl lactones

Axially chiral natural products are rewarding synthetic targets, due to their wide distribution, diverse structures, and promising bioactivities. The "lactone concept" provides an efficient strategy for the regio- and stereoselective construction of even bulky biaryls. Key steps are the intramolecular coupling of the ester-prefixed molecular portions to give (mostly configurationally unstable) biaryl lactones and their stereoselective ring cleavage (usually by dynamic kinetic resolution), leading to the one or-optionally-the other atropisomeric product from the same lactone. Stereoisomeric byproducts can be recycled by recyclization back to the lactone. The broad applicability of the method is demonstrated in the total synthesis of selected representatives from five very different classes of natural biaryl products.     

Synthesis and Biological Evaluation of New (−)‐Englerin Analogues

We report the synthesis and biological evaluation of a series of (?)‐englerin A analogues obtained along our previously reported synthetic route based on a stereoselective gold(I) cycloaddition process. This synthetic route is a convenient platform to access analogues with broad structural diversity and has led us to the discovery of unprecedented and easier‐to‐synthesize derivatives with an unsaturation in the cyclopentyl ring between C4 and C5. We also introduce novel analogues in which the original isopropyl motif has been substituted with cyclohexyl, phenyl, and cyclopropyl moieties. The high selectivity and growth‐inhibitory activity shown by these new derivatives in renal cancer cell lines opens new ways toward the final goal of finding effective drugs for the treatment of renal cell carcinoma (RCC).     

Synthetic Studies toward Communesins

Communesins A–H are a growing family of natural products isolated from a marine fungal strain of Penicillium species. Preliminary biological evaluation has revealed that these compounds possess insecticidal activity and cytotoxicity against several tumor cell lines. Their interesting biological activities and unique structures have attracted considerable attention of synthetic chemists worldwide. To date, several elegant protocols for assembling the core structure of these indole alkaloids have been described, including intermolecular Diels–Alder reaction of methylated aurantioclavine with quinine methide imine and intramolecular hetero Diels–Alder reaction of the azaortho-xylylene intermediates. Recently, three completed total syntheses for communesin F have been disclosed, in which the crucial vicinal quaternary stereogenic centers were constructed by employing an intramolecular cyclopropanation; an intramolecular Heck reaction of a tetrasubstituted alkene, or an oxidative coupling of a 3-substituted indole, as the key step. Accompanying the total synthesis, the absolute configuration of natural communesin F was established as 6R,7R,8R,9S,11R. However, total syntheses of other members of communesin family that contain an epoxide moiety have not been achieved, which will stimulate more synthetic studies.     

Isodesmic Reactions in Catalysis – Only the Beginning?

In this perspective article, we discuss catalytic isodesmic reactions, a group of chemical reactions that proceed through the redistribution of chemical bonds – i. e. all bonds present in the starting materials are reformed in the products. These reactions are usually reversible and provide a complementary approach to the kinetically controlled strategies traditionally employed in chemical synthesis. To emphasize the power of these reactions across the molecular sciences, we present selected applications of these reactions in organic synthesis, chemical biology, biomass valorization, waste treatment, and materials science. We finally speculate that the development of novel catalytic isodesmic reactions beyond the “classics” (alkene/alkyne metathesis and transfer hydrogenation) holds great promise to solve crucial challenges in synthetic chemistry in the years to come.     

An Efficient Synthesis of 3-Alkylpyridine Alkaloids Enables Their Biological Evaluation

3-Alkylpyridine alkaloids (3-APAs) isolated from the arctic sponge Haliclona viscosa are a promising group of bioactive marine alkaloids. However, due to limited bioavailability, investigations of their bioactivity have been hampered. Additionally, synthesis of a common intermediate requires the use of protecting groups and harsh conditions. In this work, we developed a simple and concise two-step route to nine different natural and synthetic haliclocyclins. These compounds displayed modest antibiotic activity against several Gram-positive bacterial strains.     

Concise Catalytic Asymmetric Total Synthesis of Biologically Active Tropane Alkaloids

A general strategy for the total asymmetric synthesis of valuable tropane alkaloids by catalytic stereoselective transformations is disclosed. The power of this approach is exemplified by the concise catalytic enantioselective total syntheses of (+)‐methylecgonine, (−)‐cocaine and (+)‐cocaine as well as the first catalytic asymmetric total syntheses of a cocaine C‐1 derivative and (+)‐ferruginine starting from 5‐oxo‐protected‐α,β‐unsaturated enals using only two and three column chromatographic purification steps, respectively.     

Paraherquamides,brevianamides, and asperparalines: laboratory synthesis and biosynthesis. An interim report

Studies from our laboratories on the paraherquamide, brevianamide, and asperparaline families of natural products are reviewed. It has been proposed that the unique core ring system that is common to this family of compounds arises by a biological intramolecular Diels-Alder cycloaddition reaction. Key biosynthetic studies are described, along with classical synthetic approaches as well as those inspired by Nature for the synthesis of these interesting molecules.