Showing papers on "Total synthesis published in 2018"

Recent advances in the application of Diels-Alder reactions involving o-quinodimethanes, aza-o-quinone methides and o-quinone methides in natural product total synthesis.

Abstract: In recent decades, transient and highly reactive ortho-quinodimethanes (o-QDMs), ortho-quinone methides (o-QMs) and aza-ortho-quinone methides (aza-o-QMs) have attracted much attention and have been extensively studied and applied in organic synthesis, especially natural product total synthesis. This review summarizes recent advances in Diels–Alder reactions involving in situ-generated o-QDMs, o-QMs and aza-o-QMs, highlighting the power and potential of this strategy in organic synthesis and natural product total synthesis. An overview of the methods for generating these intermediates is also available.

Radicals in natural product synthesis

Abstract: Free radical intermediates have intrigued chemists since their discovery, and an ever-increasing appreciation for their unique reactivity has resulted in the widespread utilization of these species throughout the field of chemical synthesis. This is most evident from the recent surge in the application of intermolecular radical reactions that feature in complex molecule syntheses. This tutorial review will discuss the diverse methods utilized for radical generation and reactivity to form critical bonds in natural product total synthesis. In particular, stabilized (e.g. benzyl) and persistent (e.g. TEMPO) radicals will be the primary focus.

Gold Catalysis for Heterocyclic Chemistry: A Representative Case Study on Pyrone Natural Products

Abstract: 2-Pyrones and 4-pyrones are common structural motif in bioactive natural products. Traditional methods for their synthesis, which try to emulate the biosynthetic pathway of cyclization of a 1,3,5-tricarbonyl precursor, are often harsh and therefore not particularly suitable for applications to polyfunctionalized and/or sensitive target compounds. -Acid catalysis, in contrast, proved much more adequate for a systematic exploration of the pyrone estate. To this end, alkynes are used as stable ketone surrogates, which can be activated under exceedingly mild conditions due to the pronounced carbophilicity of LAu+ (L = two electron donor ligand); intramolecular attack of a tethered ester carbonyl group onto the transient alkyne-gold complex then forges the pyrone ring in a fully regiocontrolled manner. This new methodology proved instrumental for the total synthesis of various natural products, including the very sensitive cyclophane neurymenolide A and an unnamed sibling thereof, the polyunsaturated C-glycosidic polyene derivative orevactaene, and the highly cytotoxic macrolide DMDA-pateamine A. The latter synthesis features an unorthodox sequence of a gold catalyzed pyrone formation followed by an iron catalyzed pyrone ring opening/cross coupling reaction. From the conceptual viewpoint, these cases studies are thought to be representative for the many inherent advantages that pi-acid catalysis can provide for contemporary heterocyclic chemistry.

Total Synthesis of (+)-Pleuromutilin

Abstract: An 18-step synthesis of the antibiotic (+)-pleuromutilin is disclosed. The key steps of the synthesis include a highly stereoselective SmI2-mediated cyclization to establish the eight-membered ring and a stereospecific transannular [1,5]-hydrogen atom transfer to set the C10 stereocenter. This strategy was also used to prepare (+)-12-epi-pleuromutilin. The chemistry described here will enable efforts to prepare new mutilin antibiotics.

Recent progress of C-glycosylation methods in the total synthesis of natural products and pharmaceuticals

Abstract: Chemical C-glycosylation has been well developed to improve stereoselectivity in recent years. Due to its high efficiency to build C-glycosides or O-cyclic compounds, C-glycosylation has found widespread use in the synthesis of biologically active molecules. This review highlights the C-glycosylation methods that have been practised in the total synthesis of natural products and pharmaceuticals in the past decade.

Total Synthesis of Hybridaphniphylline B

Abstract: Hybridaphniphylline B (1) is a Daphniphyllum alkaloid possessing 11 rings and 19 stereocenters. Here we report the first total synthesis of 1 featuring a late-stage intermolecular Diels–Alder reaction of a fully elaborated cyclopentadiene and asperuloside tetraacetate. The diene was prepared on the basis of a scalable route to daphnilongeranin B (4). Claisen rearrangement of an allyl dienol ether was exploited as a key step; the subtle variation of the substrate and use of protic solvents suppressed the undesired Cope rearrangement. Daphniyunnine E (6) and dehydrodaphnilongeranin B (7), two congeners of 4, were also synthesized. The dienophile arose from (+)-genipin through glycosylation and lactonization. A one-pot protocol was developed for the diene formation and Diels–Alder reaction; one of the cycloadducts was converted into 1 through reductive desulfurization and global deacetylation.

Total synthesis of complex alkaloids by nucleophilic addition to amides.

Abstract: Nucleophilic addition to amides has been recognized as a promising transformation for total synthesis of complex alkaloids. Amides can accept two different organometallic reagents through the nucleophilic addition, which enables it to serve as a stable surrogate of multi-substituted amines. However, the nucleophilic addition has been overlooked for a long time due to three main reasons: low electrophilicity of amide carbonyls, potential hydrolysis of the reaction intermediate and excess addition of an organometallic reagent. This mini review focuses on the recent progress of total synthesis of complex alkaloids based on the nucleophilic additions to N-alkoxyamides, tertiary amides and secondary amides.

Divergent Total Syntheses of (−)-Daphnilongeranin B and (−)-Daphenylline

Abstract: (-)-Daphnilongeranin B and (-)-daphenylline are two hexacyclic Daphniphyllum alkaloids, each containing a complex cagelike backbone. Described herein are the first asymmetric total synthesis of (-)-daphnilongeranin B and a bioinspired synthesis of (-)-daphenylline with an unusual E ring embedded in a cagelike framework. The key features include an intermolecular [3+2] cycloaddition, a late-stage aldol cyclization to install the F ring of daphnilongeranin B, and a bioinspired cationic rearrangement leading to the tetrasubstituted benzene ring of daphenylline.

Catalytic approaches to assemble cyclobutane motifs in natural product synthesis

Abstract: Cyclobutanes, as the second most strained monocyclic all-carbon rings, are found in many complex natural products. Although recent methodological developments in the formation of cyclobutanes have been reviewed, few have focused on the topic of total synthesis of cylcobutane-containing natural products. Here we summarize recent advances in natural product synthesis, featuring late-stage functionalization of four-membered rings and novel strategies for the stereocontrolled assembly of cyclobutanes or cyclobutenes.

Organo-Cation Catalyzed Asymmetric Homo/Heterodialkylation of Bisoxindoles: Construction of Vicinal All-Carbon Quaternary Stereocenters and Total Synthesis of (−)-Chimonanthidine

Abstract: A novel chiral spirocyclic amide (SPA)-derived triazolium organocatalyst has been designed and demonstrated to effect asymmetric homo- and heterodialkylations of various bisoxindoles, enabling enantioselective construction of vicinal all-carbon quaternary stereocenters. These reactions feature excellent enantio- and diastereoselectivities (up to 99% ee and >20:1 dr) as well as good to high yields (up to 89% over two steps). As an application of this methodology, the first asymmetric total synthesis of (-)-chimonanthidine has been achieved.

Concise Synthesis of (−)-Cycloclavine and (−)-5-epi-Cycloclavine via Asymmetric C–C Activation

Abstract: To illustrate the synthetic significance of C–C activation methods, here we describe an efficient strategy for the enantioselective total syntheses of (−)-cycloclavine and (−)-5-epi-cycloclavine, which is enabled by an asymmetric Rh-catalyzed “cut-and-sew” transformation between benzocyclobutenones and olefins. Despite the compact structure of cycloclavine with five-fused rings, the total synthesis was accomplished in 10 steps with a 30% overall yield. Key features of the synthesis include (1) a Pd-catalyzed tandem C–N bond coupling/allylic alkylation sequence to construct the nitrogen-tethered benzocyclobutenone, (2) a highly enantioselective Rh-catalyzed carboacylation of alkenes to forge the indoline-fused tricyclic structure, and (3) a diastereoselective cyclopropanation for preparing the tetrasubstituted cyclopropane ring. Notably, an improved catalytic condition has been developed for the nitrogen-tethered cut-and-sew transformation, which uses a low catalyst loading and allows for a broad substrate...

Beyond olefins: new metathesis directions for synthesis.

Abstract: The olefin-olefin metathesis reaction has emerged as one of the most important carbon-carbon bond-forming reactions, as illustrated by its wide use in the synthesis of complex molecules, natural products and pharmaceuticals. The corresponding metathesis reaction between carbonyls and olefins or alkynes similarly allows for the formation of carbon-carbon bonds. Although these variants are far less developed and utilized in organic synthesis, they possess attractive qualities that have prompted chemists to incorporate and explore these modes of reactivity in complex molecule synthesis. This review highlights selected examples of carbonyl-olefin and carbonyl-alkyne metathesis reactions in organic synthesis, in particular in the total synthesis of natural products and complex molecules, and provides an overview of current advantages and limitations.

Total Synthesis of (±)-Cephanolides B and C via a Palladium-Catalyzed Cascade Cyclization and Late-Stage sp3 C-H Bond Oxidation.

Abstract: Herein, we report the first total syntheses of complex cephalotaxus diterpenoids cephanolide B and C from commercially available 5-bromo-2-methylanisole. Key to the success of this synthetic route is a palladium-catalyzed cascade cyclization reaction, which allowed us to efficiently forge the 6–5–6 cis-fused tricyclic ring systems found in the entire family of cephalotaxus diterpenoids. Additionally, site-selective late-stage sp3 C–H bond oxidation served as a key strategic element in the chemical synthesis of cephanolide C.

Application of asymmetric Sharpless aminohydroxylation in total synthesis of natural products and some synthetic complex bio-active molecules

Abstract: This report illustrates the applications of Asymmetric Sharpless Aminohydroxylation (ASAH) in the stereoselective synthesis of vicinal amino alcohols as important intermediates in the total synthesis of complex molecules and natural products with significant biological activities The ASHA allows the regio- syn-selective synthesis of 1,2-amino alcohols via reaction of alkenes with salts of N-halosulfonamides, -amides and -carbamates employing osmium tetroxide (OsO4) as an efficient catalyst In this reaction, chirality is induced via the addition of dihydroquinine- and dihydroquinidine as derived chiral ligands

Stereoselective Reactions of ortho-Quinone Methide and ortho-Quinone Methide Imines and Their Utility in Natural Product Synthesis

Abstract: Herein presented is a review of the reactivity and synthetic utility of ortho-quinone methides and ortho-quinone methide imines. These versatile intermediates have received significant attention in the literature and new methods for their preparation and reaction as well as recent applications in total synthesis are discussed. 1 Introduction 2 Conjugate Addition Reactions 3 Concerted Cycloaddition Reactions 4 Stepwise Addition Reactions 5 Applications in Total Synthesis 6 Conclusion

Recent Advances in Total Synthesis via Metathesis Reactions

Abstract: The metathesis reactions, in their various versions, have become a powerful and extremely valuable tool for the formation of carbon–carbon bonds in organic synthesis. The plethora of available catalysts to perform these reactions, combined with the various transformations that can be accomplished, have positioned the metathesis processes as one of the most important reactions of this century. In this review, we highlight the most relevant synthetic contributions published between 2012 and early 2018 in the field of total synthesis, reflecting the state of the art of this chemistry and demonstrating the significant synthetic potential of these methodologies. 1 Introduction 2 Alkene Metathesis in Total Synthesis 2.1 Total Synthesis Based on a Ring-Closing-Metathesis Reaction 2.2 Total Synthesis Based on a Cross-Metathesis Reaction 2.3 Strategies for Selective and Efficient Metathesis Reactions of Alkenes 2.3.1 Temporary Tethered Ring-Closing Metathesis 2.3.2 Relay Ring-Closing Metathesis 2.3.3 Stereoselective Alkene Metathesis 2.3.4 Alkene Metathesis in Tandem Reactions 3 Enyne Metathesis in Total Synthesis 3.1 Total Syntheses Based on a Ring-Closing Enyne-Metathesis Reaction 3.2 Total Syntheses Based on an Enyne Cross-Metathesis Reaction 3.3 Enyne Metathesis in Tandem Reactions 4 Alkyne Metathesis in Total Synthesis 4.1 Total Synthesis Based on a Ring-Closing Alkyne-Metathesis Reaction 4.2 Other Types of Alkyne-Metathesis Reactions 5 Conclusions

A Unified Approach for the Assembly of Atisine- and Hetidine-type Diterpenoid Alkaloids: Total Syntheses of Azitine and the Proposed Structure of Navirine C

Abstract: A tetracyclic dinitrile was synthesized in twelve steps from cyclohex-2-en-1-one by using a chelation-triggered conjugate addition to a γ-hydroxy-substituted α,β-unsaturated nitrile and an oxidative dearomatization/Diels-Alder cycloaddition cascade as the key steps. The first total synthesis of azitine (in 17 steps) was achieved through a simple reductive cyclization of this intermediate and subsequent transformations while the total synthesis of the proposed structure of navirine C (in 19 steps) was accomplished by a hydrogen-atom-transfer reaction of the tetracyclic dinitrile, Pd/C-catalyzed reductive cyclization, and subsequent functional group manipulation.

Unified Total Synthesis of Pyrroloazocine Indole Alkaloids Sheds Light on Their Biosynthetic Relationship

Abstract: The total synthesis of seven members of the lapidilectine and grandilodine family of alkaloids has been accomplished in racemic and enantiopure form without protection/deprotection of functional groups. The two key steps, an 8- endo-dig hydroarylation and a 6- exo-trig photoredox cyclization, were catalyzed using gold. A rationale for the formation of the cyclopropane ring of the lundurines is also provided.

Asymmetric Total Synthesis of Cyclocitrinol

Abstract: The first and asymmetric total synthesis of cyclocitrinol, an unusual C25 steroid, has been accomplished in a linear sequence of 18 steps from commercially available compound 11. The synthetically challenging bicyclo[4.4.1] A/B ring system with a strained bridgehead (anti-Bredt) double bond of cyclocitrinol was constructed efficiently and diastereoselectively via a type II intramolecular [5 + 2] cycloaddition.

Applications of Friedel–Crafts reactions in total synthesis of natural products

Abstract: Over the years, Friedel–Crafts (FC) reactions have been acknowledged as the most useful and powerful synthetic tools for the construction of a special kind of carbon–carbon bond involving an aromatic moiety. Its stoichiometric and, more recently, its catalytic procedures have extensively been studied. This reaction in recent years has frequently been used as a key step (steps) in the total synthesis of natural products and targeted complex bioactive molecules. In this review, we try to underscore the applications of intermolecular and intramolecular FC reactions in the total syntheses of natural products and complex molecules, exhibiting diverse biological properties.

Recent advances in the intramolecular Mannich reaction in natural products total synthesis

Abstract: The Mannich reaction has been widely used to effectively construct C–N and C–C bonds in organic synthesis. This review focuses on selected applications of the intramolecular Mannich reaction as a key step in the total synthesis of natural products (2000–2017). The organization of the synthetic applications is based on the structure of newly-formed skeletons using the intramolecular Mannich reaction, which include aza-fused rings and aza-bridged rings.

Total Synthesis of (−)-Xylogranatopyridine B via a Palladium-Catalyzed Oxidative Stannylation of Enones

Abstract: We report a total synthesis of the pyridine-containing limonoid alkaloid (−)-xylogranatopyridine B in 11 steps from commercially available dihydrocarvone. The central pyridine ring was assembled by a late-stage fragment coupling approach employing a modified Liebeskind pyridine synthesis. One fragment was prepared by an allyl-palladium catalyzed oxidative enone β-stannylation, in which the key bimetallic β-stannyl palladium enolate intermediate undergoes a β-hydride elimination. This methodology also allowed introduction of alkyl and silyl groups to the β-position of enones.

Application of the Asymmetric Pictet–Spengler Reaction in the Total Synthesis of Natural Products and Relevant Biologically Active Compounds

Abstract: Tetrahydroisoquinolines are the framework of numerous natural products predominantly alkaloids, an important and one of the most wide spread families of naturally occurring compounds in the plant kingdom. Tetrahydroisoquinolines are commonly constructed through an old reaction, the so-called Pictet–Spengler Reaction (PSR). In this reaction, a β-aryl ethylamine undergoes an acid mediated condensation with a suitable aldehyde or ketone, followed by ring closure. In this review, we aim to highlight the applications of the asymmetric variant of this old name reaction in the total synthesis of natural products, chiefly, alkaloids, which exhibit significant biological properties.

Heteroannulation of Arynes with α-Amino Imides: Synthesis of 2,2-Disubstituted Indolin-3-ones and Application to the Enantioselective Total Synthesis of (+)-Hinckdentine A.

Abstract: A novel heteroannulation reaction between α-amino imides and in situ generated arynes has been developed for the synthesis of 2,2-disubstituted indolin-3-ones. An enantioselective total synthesis of the marine alkaloid (+)-hinckdentine A was subsequently accomplished using this reaction as a key step. A catalytic enantioselective Michael addition of an α-aryl-α-isocyanoacetate to phenyl vinyl selenone was employed for the construction of the enantioenriched α-quaternary α-amino ester.

Iodospirocyclization of Tryptamine-Derived Isocyanides: Formal Total Synthesis of Aspidofractinine.

Abstract: The N-iodosuccinimide-mediated spirocyclization of tryptamine-derived isocyanides to generate spiroindolenines is reported. The products contain both an imine and an imidoyl iodide as flexible handles for follow-up chemistry. Nucleophilic addition typically occurs chemoselectively on the imine moiety with complete diastereoselectivity, providing opportunities for the construction of complex molecular frameworks. The synthetic potential of the method was showcased in the formal total synthesis of (±)-aspidofractinine.

Total Synthesis of (−)-Mitrephorone A

Abstract: The first synthesis of (−)-mitrephorone A is disclosed along with discussion and study of synthetic strategies. The natural product includes a highly congested hexacyclic ent-trachylobane diterpenoid framework featuring a rare, embedded oxetane. The synthetic analysis presented dissects a number of approaches for the synthesis of the central oxetane, including carbonyl-olefin photocycloadditions, Prins-type cyclizations, and oxidative ring closures. In the successful route, three [4 + 2] cycloadditions enable rapid construction of all carbocycles. A novel late-stage oxidative cyclization of a hydroxy diosphenol with Koser’s reagent furnishes the pivotal oxetane moiety.

Total Synthesis of (−)-Xishacorene B from (R)-Carvone Using a C–C Activation Strategy

Abstract: The activation of C–C bonds that are traditionally viewed as unreactive, when coupled with other bond-forming processes, can offer new approaches to the synthesis of complex molecular scaffolds In this Communication, we demonstrate the conversion of carvone to unusual bicyclo[331] and [321] frameworks by exploiting a Pd(0)-catalyzed C–C bond activation reaction and a radical cyclization process This sequence is applied to a 10-step synthesis of the diterpene xishacorene B