Concise Total Synthesis Research Articles

Asymmetric Total Synthesis of Eupalinilide E, a Promoter of Human HSPC Expansion

A concise and scalable asymmetric total synthesis of eupalinilde E from (R)-(-)-carvone in 12 steps is reported with an overall yield of 20%. The key steps of the synthesis are a tandem Favorskii rearrangement-elimination reaction in the chromatography-free synthesis of carvone-derived 2-cyclopentene carbaldehyde and its catalyst-free stereospecific tandem allylboration-lactonization using recyclable trifluoroethanol as a promoter and solvent affording β-hydroxymethyl-α-methylene-γ-butyrolactone.

Concise Total Synthesis of Dysoxylactam A and a Simplified Analog

Comprehensive SummaryA total synthesis of 17‐membered macrocyclolipopeptide dysoxylactam A, a potent agent reversing P‐glycoprotein (P‐gp)‐mediated multidrug resistance (MDR) in cancer cells, was developed from the starting material (S)‐2‐methylbutanal in a linear sequence of 12 steps with 23.2% overall yield. The key steps include proline‐catalyzed asymmetric aldol reaction, Evans aldol reaction and Krische allylation to construct the multiple stereocenters containing fragment, and ring‐closing metathesis to furnish the macrocycle. This total synthesis facilitates the preparation of large amount samples of dysoxylactam A and the side chain simplified derivatives for further biological tests and preliminary structure‐activity relationship exploration.

Taming the radical cation intermediate enabled one-step access to structurally diverse lignans

Lignans, in spite of their structural diversity, are all biosynthetically derived from coniferyl alcohol. We report herein a divergent synthesis of lignans from biomass-derived monolignols in a short synthetic sequence. Blue LED irradiation of a dichloromethane solution of dicinnamyl ether derivatives in the presence of Cu(TFA)2, an alcohol (2.0 equiv) and a catalytic amount of Fukuzumi’s salt affords the C7-alkoxylated aryltetralin cyclic ethers. Increasing the amount of alcohol under otherwise identical conditions diverts the reaction course to furnish the C7,C7’-dialkoxylated dibenzyltetrahydrofurans, while replacing Cu(TFA)2 with diphenyl disulfide (PhSSPh) provides selectively the C7-monoalkoxylated dibenzyltetrahydrofurans. Aza-, thia- and carba-analogues of lignans are equally accessible by simply changing the tethering atom of the allylic alcohols. Concise total syntheses of aglacins A, E, F, brassilignan, and dehydrodimethylconidendrin are documented featuring these transformations.

Asymmetric Total Syntheses of (-)-Lycoramine, (-)-Lycoraminone, (-)-Narwedine, and (-)-Galanthamine.

A concise asymmetric total synthesis of naturally occurring Amaryllidaceae alkaloids sharing dihydrobenzofuran scaffolds, (-)-galanthamine (1a), (-)-lycoramine (1b), (-)-narwedine (2a), and (-)-lycoraminone (2b), is reported. Orthoester Johnson-Claisen rearrangement of allyl alcohol (+)-9 (98% ee) in diisopropylethylamine furnished enantioenriched cyclohexene (+)-8 (97.4% ee) with a quaternary stereogenic center.

Total Synthesis of (+)-Tabertinggine

A concise total synthesis of (+)-tabertinggine was accomplished in 12 steps with 6.1% overall yield enabled by a Pictet-Spengler condensation/lactamization cascade reaction.

Enantioselective Total Synthesis of [3]‐Ladderanol through Late‐Stage Organocatalytic Desymmetrization**

AbstractLadderane phospholipids, with their unusual ladder‐like arrangement of concatenated cyclobutane rings, represent an architecturally unique class of natural products. However, despite their fascinating structure and other necessary impetus, only a few synthetic studies of these molecules have been reported so far. We have now devised a concise total synthesis of [3]‐ladderanol, a component of natural ladderane phospholipids, using an organocatalytic enantioselective desymmetrizing formal C(sp2)−H alkylation. Our synthetic strategy rests on the late‐stage introduction of chirality, thus allowing facile access to both enantiomers of [3]‐ladderanol as well as an analogue. This is the first time a desymmetrization strategy is applied to the synthesis of [3]‐ladderanol. The scope of this desymmetrizing C(sp2)−H alkylation of meso‐cyclobutane‐fused cyclohexenediones is also presented.

Enantioselective Total Synthesis of [3]‐Ladderanol through Late‐Stage Organocatalytic Desymmetrization**

Ladderane phospholipids, with their unusual ladder-like arrangement of concatenated cyclobutane rings, represent an architecturally unique class of natural products. However, despite their fascinating structure and other necessary impetus, only a few synthetic studies of these molecules have been reported so far. We have now devised a concise total synthesis of [3]-ladderanol, a component of natural ladderane phospholipids, using an organocatalytic enantioselective desymmetrizing formal C(sp2 )-H alkylation. Our synthetic strategy rests on the late-stage introduction of chirality, thus allowing facile access to both enantiomers of [3]-ladderanol as well as an analogue. This is the first time a desymmetrization strategy is applied to the synthesis of [3]-ladderanol. The scope of this desymmetrizing C(sp2 )-H alkylation of meso-cyclobutane-fused cyclohexenediones is also presented.

Catalytic Asymmetric Spirocyclizing Diels-Alder Reactions of Enones: Stereoselective Total and Formal Syntheses of α-Chamigrene, β-Chamigrene, Laurencenone C, Colletoic Acid, and Omphalic Acid.

We disclose a general catalytic enantioselective Diels–Alder reaction of exo-enones with dienes to give spirocyclanes. The obtained products feature highly congested quaternary stereogenic spirocenters and are used in concise total and formal syntheses of several sesquiterpenes, including of α-chamigrene, β-chamigrene, laurencenone C, colletoic acid, and omphalic acid. The stereo- and regioselectivities of our spirocyclizing cycloaddition are effectively controlled by strongly acidic and confined imidodiphosphorimidate catalysts. Computational studies shed light on the origin of reactivity and selectivity.

Concise Synthesis of (±)-Myrioneurinol Enabled by Sequential [2+2] Cycloaddition/Retro-Mannich Fragmentation/Mannich Reaction.

A concise total synthesis of (±)-myrioneurinol has been achieved in 14 steps. An efficient AgSbF6 /t-BuCl-catalyzed intramolecular [2+2] cycloaddition reaction of the alkynone-tethered enamine was developed to prepare the highly strained cyclobutene. It was used in combination with a subsequent retro-Mannich fragmentation/Mannich reaction to efficiently construct the tricyclic core of myrioneurinol.

Concise Synthesis of (±)‐Myrioneurinol Enabled by Sequential [2+2] Cycloaddition/Retro‐Mannich Fragmentation/Mannich Reaction

AbstractA concise total synthesis of (±)‐myrioneurinol has been achieved in 14 steps. An efficient AgSbF6/t‐BuCl‐catalyzed intramolecular [2+2] cycloaddition reaction of the alkynone‐tethered enamine was developed to prepare the highly strained cyclobutene. It was used in combination with a subsequent retro‐Mannich fragmentation/Mannich reaction to efficiently construct the tricyclic core of myrioneurinol.

Total Synthesis of Rucaparib.

A concise total synthesis of rucaparib, an FDA-approved drug for ovarian and prostate cancers, is reported. The Heck reaction of the commercially available aryl iodide with acrylonitrile provided the desired (E)-2-aminocinnamonitrile derivative. A subsequent imino-Stetter reaction of the aldimine derived from 2-aminocinnamonitrile and aldehyde furnished indole-3-acetonitrile bearing the desired substituents at appropriate positions. The construction of the final azepinone scaffold via reduction of the nitrile group followed by seven-membered lactamization afforded rucaparib. Notably, the synthesis of rucaparib is achieved using commercially available starting materials in only three separation operations with 54% overall yield.

Diels-Alder Reaction of Photochemically Generated (E)-Cyclohept-2-enones: Diene Scope, Reaction Pathway, and Synthetic Application.

Upon irradiation at λ = 350 nm, cyclohept-2-enone undergoes an isomerization to the strained (E)-isomer. The process was studied by XMS-CASPT2 calculations and found to proceed by two competitive reaction channels on either the singlet or the triplet hypersurface. (E)-Cyclohept-2-enone is a reactive dienophile in thermal [4 + 2] cycloaddition reactions with various dienes. Ten different dienes were probed, most of which─except for 1,3-cyclohexadiene─underwent a clean Diels-Alder reaction and gave the respective trans-fused six-membered rings in good yields (68-98%). The reactions with furan were studied in detail, both experimentally and by DLPNO-CCSD(T) calculations. Two diastereoisomers were formed in a ratio of 63/35 with the exo-product prevailing, and the configuration of both diastereoisomers was corroborated by single crystal X-ray crystallography. The outcome of the photoinduced Diels-Alder reaction matched both qualitatively and quantitatively the calculated reaction pathway. Apart from cyclohept-2-enone, five additional cyclic hept-2-enones and cyclooct-2-enone were employed in their (E)-form as dienophiles in the Diels-Alder reaction with 1,3-cyclopentadiene (80-98% yield). The method was eventually applied to a concise total synthesis of racemic trans-α-himachalene (four steps, 14% overall yield).

Bioinspired Total Synthesis of Erectones A and B, and the Revised Structure of Hyperelodione D

AbstractThe field of biomimetic synthesis seeks to apply biosynthetic hypotheses to the efficient construction of complex natural products. This approach can also guide the revision of incorrectly assigned structures. Herein, we describe the evolution of a concise total synthesis and structural reassignment of hyperelodione D, a tetracyclic meroterpenoid derived from a Hypericum plant, alongside some biogenetically related natural products, erectones A and B. The key step in the synthesis of hyperelodione D forms six stereocentres and three rings in a bioinspired cascade reaction that features an intermolecular Diels–Alder reaction, an intramolecular Prins reaction and a terminating cycloetherification.

Bioinspired Total Synthesis of Erectones A and B, and the Revised Structure of Hyperelodione D.

The field of biomimetic synthesis seeks to apply biosynthetic hypotheses to the efficient construction of complex natural products. This approach can also guide the revision of incorrectly assigned structures. Herein, we describe the evolution of a concise total synthesis and structural reassignment of hyperelodione D, a tetracyclic meroterpenoid derived from a Hypericum plant, alongside some biogenetically related natural products, erectones A and B. The key step in the synthesis of hyperelodione D forms six stereocentres and three rings in a bioinspired cascade reaction that features an intermolecular Diels–Alder reaction, an intramolecular Prins reaction and a terminating cycloetherification.

Asymmetric Total Syntheses of Strychnos Alkaloids via Selective Fischer Indolization.

The complex structures and important biological functions of Strychnos alkaloids have attracted a great deal of attention from synthetic chemists. Herein, we describe the concise asymmetric total syntheses of the Strychnos alkaloids, (-)-dehydrotubifoline, (-)-tubifoline, and (-)-tubifolidine, as well as the formal total synthesis of (-)-strychnine. Our strategy features the construction of the common tetracyclic pyrrolo[2,3-d]carbazole structure using regioselective Fischer indolization on unsymmetrical cyclic ketones and late-stage functionalization for divergent synthesis. We developed a stepwise Fischer indolization featuring selective formation of enol triflate to solve the challenging regioselectivity problem, leading to the common tetracyclic ring skeleton in these Strychnos alkaloids. The regioselectivity of Fischer indolization on unsymmetrical cyclic ketones was studied on the basis of different types of ring systems and supported by density functional theory calculations. Overall, our success in the construction of this tetracyclic ring secured the syntheses of Strychnos alkaloids and may provide a general method for the total syntheses of various alkaloids containing this skeleton.

Pd-Catalyzed Asymmetric Three-Component Allenol Carbopalladation and Allylic Cycloaddition Cascade: A Route to Functionalized Tetrahydrofurans

The first Pd-catalyzed asymmetric three-component reaction of 2,3-allenol, aryl iodides, and 2-arylmethylenemolononitriles has been developed via an allenol carbopalladation and an allylic cycloaddition cascade. This process allows rapid access to substituted tetrahydrofurans bearing diverse functional groups in good yields with high diastereoselectivities and excellent enantioselectivities. The concise total synthesis of a lignan, (-)-2-episesaminone, has been achieved by the elaboration of a functionalized tetrahydrofuran obtained from this reaction.

Cascade Benzannulation Approach for the Syntheses of Lipocarbazoles, Carbazomycins, and Related Alkaloids.

Herein, a state-of-the-art one-pot cascade benzannulation technique for the efficacious synthesis of valuable 3-hydroxy-2-methyl carbazoles, a linchpin of more than 25 carbazole-based alkaloids, is unveiled from readily affordable fundamental commodities. The key step of this strategy is gaining aromaticity by site-selective elimination of hydroxyl group controlled by nucleophilicity of the indole ring. The present strategy shows excellent functional group tolerance with a broad substrate scope. The utility of this convenient approach was appealingly exemplified via concise total syntheses of 10 carbazole-based alkaloids possessing significant biological activities and thus of medicinal importance.

Total synthesis of himastatin.

The natural product himastatin has an unusual homodimeric structure that presents a substantial synthetic challenge. We report the concise total synthesis of himastatin from readily accessible precursors, incorporating a final-stage dimerization strategy that was inspired by a detailed consideration of the compound's biogenesis. Combining this approach with a modular synthesis enabled expedient access to more than a dozen designed derivatives of himastatin, including synthetic probes that provide insight into its antibiotic activity.

Concise and efficient total synthesis of oxyphyllacinol, yakuchione-A and yakuchione-B

A concise and efficient method for the large-scale total synthesis of oxyphyllacinol (1) has been achieved in six steps with an overall yield of 46%. Simultaneously, yakuchione-A (11) was obtained in a satisfactory yield (52%) during the process. By employing a Weinreb amide (6) as the key masonry block, yakuchione-B (13) was also constructed in a great overall yield (56%) and high purity. To overcome the challenges regarding the practical scale, high purity, and reproducibility, the synthetic route that was processed takes advantage of available materials, conventional reactions, and convenient purification methods without using column chromatography.

A Concise Total Synthesis of the Fungal Isoquinoline Alkaloid TMC-120B

Recent reports of antiepileptic activity of the fungal alkaloid TMC-120B have renewed the interest in this natural product. Previous total syntheses of TMC-120B comprise many steps and have low overall yields (11–17 steps, 1.5–2.9% yield). Thus, to access this compound more efficiently, we herein present a concise and significantly improved total synthesis of the natural product. Our short synthesis relies on two key cyclization steps to assemble the central scaffold: isoquinoline formation via an ethynyl-imino cyclization and an intramolecular Friedel-Crafts reaction to form the furanone.