Synthesis of Terpenoids. III. Total Syntheses of α-Bisabololone and α-Trans-Atlantone

Recently, anions of “protected” cyanohydrins have been introduced as useful acyl carbanions equivalents in organic synthesis². Continuing with our interest in the use of these reagents for natural product syntheses³, we wish to report a short total synthesis of the sesquiterpene α-bisabololone 1 ^4,5, whose salient feature is a novel application of “protected” cyanohydrins to the synthesis of β-hydroxy ketones.     

Total Syntheses of Kopsaporine,Kopsinol and Kopsiloscine A

Kopsia alkaloids represent a complex class of natural products bearing a polycyclic ring system with two or three consecutive quaternary carbon centers. In this article, we report the first total synthesis of Kopsaporine related alkaloids. Features of our structure-unit-based strategy are an intramolecular Pummerer rearrangement induced nucleophilic cyclization/aza-Prins cyclization to construct the highly functional hexahydrocarbazole skeleton, an olefin migration vinylogous alkylation to establish the C20 all-carbon quaternary center, an iridium complex mediated radical addition to fuse the aspidofractine framework, an unprecedented IBX oxidation to introduce the α-hydroxyketone moiety, and a bioinspired retro-Aldol/Aldol reaction to convert kopsaporine to kopsiloscine A.     

Equilibrium Studies of Binary and Ternary Complexes Involving Tricine and Some Selected α-Amino Acids

Summary. The formation equilibria for the binary complexes of Co^II, Ni^II, Cu^II, Zn^II, Cd^II, Mn^II, Pb^II, Th^IV, UO₂^II, and Ce^III with tricine and for the ternary complexes involving some -amino acids (glycine, -alanine, proline, serine, asparagine, and aspartic acid) were investigated using pH-metric technique. The formation of binary and ternary complexes was inferred from the pH-metric titration curves. It was deduced that tricine acts as a primary ligand in the ternary complexes involving the monocarboxylic amino acids (glycine, -alanine, proline, serine, and asparagine), whereas it behaves as a secondary ligand in the ternary systems containing the dicarboxylic aspartic acid. The ternary complex formation was found to take place in a stepwise manner. The stability constants of the complexes formed in aqueous solutions were determined potentiometrically under the experimental conditions (t=25°C, I=0.1moldm^–3 NaNO₃). The order of stability of the ternary complexes in terms of the nature of the amino acids is investigated and discussed. The values of log K for the ternary complexes have been evaluated and discussed. Evaluation of the effects of ionic strength and temperature of the medium on the stability of the ternary system M^II-tricine--alanine (M^II=Co^II, Ni^II, and Cu^II) has been studied. The thermodynamic parameters were calculated and discussed.     

Divergent Total Syntheses of (−)-Daphnezomines A and B and (+)-Dapholdhamine B

The daphnezomine A-type subfamily of Daphniphyllum alkaloids structurally features a unique aza-adamantane core skeleton and anticipates efficient strategies for completing their syntheses to thoroughly investigate their biological activities. Herein, divergent total syntheses of (−)-daphnezomines A and B and (+)-dapholdhamine B have been accomplished in 16–20 steps from a known epoxide via rapid construction of a common core intermediate. The present work features a Ti-mediated radical cyclization to establish the azabicyclo[3.3.1]nonane ring system, an intramolecular Heck reaction to install the bridgehead all-carbon quaternary stereocenter, a tandem deprotection/reduction/keto amine-carbinolamine tautomerization to furnish the aza-adamantane backbone, and an NIS-promoted 6-endo-trig aminocyclization to assemble the (+)-dapholdhamine B backbone.     

Unified Asymmetric Total Syntheses of (−)-Alotaketals A–D and (−)-Phorbaketal A

The novel tricyclic spiroketal alotane-type sesterterpenoids showed strikingly different biological activities and potency with subtle structural alterations. Asymmetric total syntheses of the tricyclic sesterterpenoids (−)-alotaketals A–D and (−)-phorbaketal A were accomplished [29–31 steps from (−)-malic acid] in a collective way for the first time. The key features of the strategy included 1) a new cascade cyclization of vinyl epoxy δ-keto-alcohols to forge the common tricyclic spiroketal intermediate, 2) a late-stage allylic C−H oxidation, and 3) olefin cross-metathesis to install the different side chains.     

Is There No End to the Total Syntheses of Strychnine? Lessons Learned in Strategy and Tactics in Total Synthesis

From the 19th century to the present, the complex indole alkaloid strychnine has engaged the chemical community. In this Review, we examine why strychnine has been and remains today an important target for directed synthesis efforts. A selection of the diverse syntheses of strychnine is discussed with the aim of identifying their influence on the evolution of the strategy and tactics of organic synthesis.     

Natural α-Amino Acid L-Lysine–Catalyzed Knoevenagel Condensations of α,β-Unsaturated Aldehydes and 1,3-Dicarbonyl Compounds

Knoevenagel condensations of α,β-unsaturated aldehydes and 1,3-dicarbonyl compounds were catalyzed by primary natural amino acid L-lysine. The reactions were carried out at room temperature in dimethylsulfoxide. It provides a facile entry to a wide variety of α,β,γ,δ-unsaturated dicarbonyl compounds.

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Synthetic Utility of α-Stannyl α,β-Unsaturated Esters as Reagents for β-Substituted Acrylate α-Anion Synthons: Tin-Lithium Exchange and Palladium-Catalized Coupling Reactions

The tin-lithium exchange and the palladium-catalized coupling reactions of the title compounds have been studied. The latter reaction was found to be more efficient for functionalizing the α-carbon of these esters.     

Asymmetric Synthesis of α, α′-Disubstituted α-Amino Acids Based on Natural (1R)-( + )-Camphor

Optically active nonproteinogenic amino acids[ 1] are valuable compounds of high interest not only owing to their remarkable pharmacological and biological activities, but also for their role as an investigative topographic probe for bioactive conformations of peptides and the mechanisms of enzyme reactions.[2]     

A New and Efficient Synthesis of α-Amino Cycloalkyl-Phosphonic Acids via Electrophilic Azidation of Cycloalkylphosphonates

α-Amino cyclobutyl-, cyclopentyl-and cyclohexylphosphonic acids (13) were efficiently prepared from the related unsubstituted cycloalkylphosphonates (5), in three steps including electrophilic azidation of the corresponding lithiated carbanions, catalytic hydrogenation of the intermediate α-azido cycloalkyl-phosphonates (10) and acidic hydrolysis of the resulting α-amino cycloalkyl-phosphonates (12).     

Synthetic studies towards(-)-deserpidine:Total synthesis of the stereoisomer and derivative of (-)-deserpidine

The asymmetric synthesis of 16,17,20-epi-deserpidine and a derivative of(-)-deserpidine has been achieved.Key feature s in the assembly of the pentacyclic framework include a visible-light photocatalytic intra-/inter-/intramolecular radical cascade reaction to construct the tetracyclic ABCD ring system in one-pot and an intramolecularaldol reaction to forge the cyclohexane E ring.     

Total Syntheses of the Chlorinated β‐Carboline Alkaloids Bauerine A,B, and C

The first total synthesis of the chlorinated 1‐oxo‐β‐carboline alkaloid bauerine C based on a Japp–Klingemann reaction is reported. An intermediate of this synthesis was converted to the fully aromatic β‐carboline bauerine B, and the related alkaloid bauerine A was prepared in an analogous manner.     

Bent π-Conjugation within a Macrocycle: Asymmetric Total Syntheses of Spirohexenolides A and B

Macrocycles with bent π-conjugation motif are extremely rare in nature and synthetically daunting and anticancer haouamines and spirohexenolides were representative of such rare natural products with synthetically challenging bent π-conjugation within a macrocycle. While the total synthesis of haouamines has been elegantly achieved, spirohexenolides remains an unmet synthetic challenge due to the highly strained bent 1,3,5-triene conjugation within C15 macrocycle. Inspired by the chemical synthesis of cycloparaphenylenes (CPPs) and haouamines, herein we devise a synthetic strategy to overcome the highly strained bent 1,3,5-triene conjugation within the macrocycle and achieve the first, asymmetric total synthesis of spirohexenolides A (>20 mg) and B (>50 mg). Our synthesis features strategic design of ring-closing metathesis (RCM) macrocyclization followed by double dehydration to achieve the C15 macrocycle with the deformed nonplanar 1,3,5-triene conjugation. In addition, we have developed a new enantioselective construction of highly functionalized spirotetronate fragment (northeast moiety) through RCM and Ireland–Claisen rearrangement. Our in vitro bioassay studies reveal that both spirohexenolides are cytotoxic against a panel of human cancer cells with IC₅₀ 1.2–13.3 μM and spirohexenolide A is consistently more potent (up to 3 times) than spirohexenolide B, suggesting the importance of alcohol for their bioactivity and for medicinal chemistry development.     

Protonation Equilibria of Some Selected α-Amino Acids in DMSO–Water Mixture and Their Cu(II)-Complexes

The protonation constants of some α-amino acids (glycine (Gly), l-alanine (Ala), l-valine (Val), l-serine (Ser), l-leucine (Leu) and l-isoleucine (Ile)) were studied in water and DMSO–water solution mixtures containing 30, 50 and 70 vol-% DMSO; in addition the complex formation equilibria of their copper(II) complexes were studied by potentiometric technique using a combined pH electrode system calibrated in concentration units of the hydrogen ion at 25 ± 0.1 °C under a nitrogen atmosphere, and at an ionic strength of 0.10 mol·dm^?3 NaNO₃. The protonation constants and the overall stability constants of copper(II) complexes were influenced by changes in solvent composition, and their variations are discussed in terms of solvent and structural properties.     

Divergent Biomimetic Total Syntheses of Ganocins A–C,Ganocochlearins C and D,and Cochlearol T

A divergent synthetic approach to six Ganoderma meroterpenoids, namely ganocins A–C, ganocochlearins C and D, and cochlearol T, has been developed for the first time. This synthetic route features a two-phase strategy which includes early-stage rapid construction of a common planar tricyclic intermediate followed by highly selective late-stage transformations into various Ganoderma meroterpenoids. Key to the strategy are a bioinspired intramolecular hetero-Diels–Alder reaction and Stahl-type oxidative aromatization, allowing efficient formation of the common tricyclic phenol intermediate. A nucleophilic dearomatization of the phenol unit, combined with a regioselective 1,4-reduction of the resulting dienone, enabled rapid access to ganocins B and C. Additionally, site-selective Mukaiyama hydration, followed by an intramolecular oxa-Michael addition/triflation cascade, served as a key strategic element in the chemical synthesis of ganocin A.     

Synthesis of Some Novel Nonionic Ethoxylated Surfactants Based on α-Amino Acids and Investigation of Their Surface Active Properties

Eight novel ethoxylated nonionic surfactants were prepared based on oil soluble α-amino acids. The L-phenylalanine and L-leucine were esterified and amidated with cetyl alcohol and palamitic acid, respectively; two amides and two esters of α-amino acids were obtained. The ethylene oxide was condensed with the prepared amides and esters to get three different polyethylene oxide units (40, 60, and 100) as phenylalanine derivatives. The amide and ester of α-L-leucine were ethoxylated at (60 ethylene oxides units). The analytical micro analysise, FTIR, ¹H NMR, ¹³C NMR, mass spectra were carried out to confirm the chemical structures. The surface tension of the water soluble prepared compounds was measured at 25°C, further the surface active properties were determined and calculated. Such that critical micelle concentration (CMC), surface excess (Γ_max); area per molecule (A_min), effectiveness (γ_CMC) free energy of micellization and adsorption (ΔG_mic, ΔG_ad). From the data obtained it was found that the CMC of phenylalanine esters is greater than that obtained for the amide derivatives. The Γ_max decreased as the ethylene oxide units (EO) increased. It was found also that the ΔG_ad was greater than the ΔG_mic. The obtained data and discrepancy were discussed on the light of surfactant chemical structure.     

Study on the Total Synthesis of Ecteinascidin 743 and Its Analogues-Construction of A Pentacyclic Intermediate

A concise and efficient synthesis of the pentacyclic intermediate 1,as a simple model compound of Ecteinascidin 743 and its analogues,is described.     

Scalable Total Syntheses and Structure–Activity Relationships of Haouamines A,B, and Their Derivatives as Stable Formate Salts

Haouamines A, B, and their derivatives were synthesized via Suzuki–Miyaura coupling and three key cyclization reactions as follows: the newly developed palladium(0)-catalyzed arylative cyclization of phenylalanine-derived alkyne–aldehydes with 2-bromoarylboronic acid (an “anti-Wacker”-type cyclization); BF₃ ⋅ OEt₂-promoted Friedel–Crafts-type cyclization of symmetrical electron-rich aromatic rings adjacent to a tertiary allylic alcohol leading to the indeno-tetrahydropyridine skeleton; and (cyanomethyl)trimethylphosphonium iodide-mediated macrocyclization of amino alcohols to afford aza-paracyclophane precursors. The palladium-catalyzed reduction of mono- and di-triflate intermediates in the later stages enabled the alteration of both the position and number of hydroxyl groups on the C-ring. The instability of haouamine B was dramatically improved by salt formation with formic acid. An unambiguous evaluation of the cytotoxicity of the prepared haouamine derivative formates with and without hydroxyl groups at different positions on the C-ring indicated that the catechol structure in haouamine B produced weak cytotoxicity.     

A Concise and Scalable Strategy for the Total Synthesis of Dictyodendrin B Based on Sequential C?H Functionalization

A sequential C H functionalization strategy for the synthesis of the marine alkaloid dictyodendrin B is reported. Our synthesis begins from commercially available 4‐bromoindole and involves six direct functionalizations around the heteroarene core as part of a gram‐scale strategy towards the natural product.