Total synthesis of (+)-lithospermic acid by asymmetric intramolecular alkylation via catalytic C-H bond activation

The total synthesis of (+)-lithospermic acid is described. The efficient synthesis features an asymmetric alkylation via C-H bond activation to assemble the dihydrobenzofuran core of the natural product. This was accomplished via a chiral imine-directed C-H bond functionalization and represents the first application of this C-H activation method to natural product synthesis. Furthermore, a challenging deprotection of a late-stage permethylated lithospermic acid was achieved.     

Asymmetric synthesis of (-)-incarvillateine employing an intramolecular alkylation via Rh-catalyzed olefinic C-H bond activation

An asymmetric total synthesis of (-)-incarvillateine, a natural product having potent analgesic properties, has been achieved in 11 steps and 15.4% overall yield. The key step is a rhodium-catalyzed intramolecular alkylation of an olefinic C-H bond to set two stereocenters. Additionally, this transformation produces an exocyclic, tetrasubstituted alkene through which the bicyclic piperidine moiety can readily be accessed.     

Bioinspired Synthesis of (−)‐PF‐1018

The combination of electrocyclizations and cycloadditions accounts for the formation of a range of fascinating natural products. Cascades consisting of 8π electrocyclizations followed by a 6π electrocyclization and a cycloaddition are relatively common. We now report the synthesis of the tetramic acid PF‐1018 through an 8π electrocyclization, the product of which is immediately intercepted by a Diels–Alder cycloaddition. The success of this pericyclic cascade was critically dependent on the substitution pattern of the starting polyene and could be rationalized through DFT calculations. The completion of the synthesis required the instalment of a trisubstituted double bond by radical deoxygenation. An unexpected side product formed through 4‐exo‐trig radical cyclization could be recycled through an unprecedented triflation/fragmentation.     

Bioinspired Synthesis of (−)-PF-1018

The combination of electrocyclizations and cycloadditions accounts for the formation of a range of fascinating natural products. Cascades consisting of 8π electrocyclizations followed by a 6π electrocyclization and a cycloaddition are relatively common. We now report the synthesis of the tetramic acid PF-1018 through an 8π electrocyclization, the product of which is immediately intercepted by a Diels–Alder cycloaddition. The success of this pericyclic cascade was critically dependent on the substitution pattern of the starting polyene and could be rationalized through DFT calculations. The completion of the synthesis required the instalment of a trisubstituted double bond by radical deoxygenation. An unexpected side product formed through 4-exo-trig radical cyclization could be recycled through an unprecedented triflation/fragmentation.     

Asymmetric total synthesis of ent-cyclooroidin

An enantiospecific total synthesis of the pyrrole-imidazole natural product cyclooroidin from histidine is described. The key N1-C9 bond is constructed through an intramolecular SN2-type of reaction of a chloro ester. Subsequent imidazole azidation at the 2-position, pyrrole bromination, azide reduction, and deprotection leads to the completion of the synthesis.     

Iron-catalyzed C–H amination and its application in organic synthesis

Transition-metal-catalyzed direct C–H bond amination is an attractive strategy in preparation of nitrogen containing molecules which are common in naturally occurring and pharmaceutically important compounds. Comparing to the precious metals commonly used in this reaction, non-precious metals such as iron are abundant in earth, relatively low toxic, and more biocompatible, which meet the increasing demand for environmentally benign and sustainable chemical processes. In this review, we described the development in iron catalyzed C–H bond amination reactions from historical landmarks to recent achievements, and placed emphasis on their applications in organic synthesis, i.e. natural product synthesis and/or modification.     

Cascade Syntheses Routes to the Centrocountins

Cascade and domino reactions that proceed through multiple steps in one pot and include multiple bond formations are promising methods for the rapid and efficient generation of complex molecular architectures, including the scaffolds of classes of complex natural product. We describe the development of various one‐pot cascade reaction sequences to yield centrocountins, which are tetracyclic indole derivatives with the basic scaffold of numerous polycyclic alkaloids. The mechanistic investigation of a sequence employing readily available alkynes and 3‐formylchromones as starting materials provided evidence that this one‐pot synthesis proceeds through at least twelve consecutive transformations and includes at least nine different chemical reactions, making it the longest cascade reaction sequence known to date. We describe the scope and limitations of the cascade synthesis approaches and the development of an enantioselectively catalyzed centrocountin synthesis.     

Total synthesis of newbouldine via reductive N-N bond formation

The first total synthesis of newbouldine has been achieved employing a new, reductive N-N bond forming reaction. The asymmetric synthesis confirms that the natural product is a racemate.     

Novel cycloalkene indole carbazole alkaloids via the ring closing metathesis reaction

Methodology for the synthesis of a series of carbocyclic indole carbazole natural product analogs is presented. The chemistry involves construction of the core indole, followed by attachment of double bond tethered side chains of three and four carbon lengths. The bottom carbocyclic ring system is formed through a ring closing metathesis reaction, and allows the installation of four, five, and six member ring sizes.     

Synthesis of plagiochiline N from santonin.

This article reports the transformation of O-acetylisophotosantonin, obtained by photochemical rearrangement of santonin, into plagiochiline N, an ent-2,3-secoaromadendrane isolated from Plagiochila ovalifolia. The synthesis was carried out in a sequence involving as the key steps (a) the substitution of the lactone moiety by a gem-dimethylcyclopropane ring through a synthetic intermediate having a C(6)-C(7) double bond and (b) the ozonolysis of the C(2)-C(3) bond followed by cyclization to the dihydropyran ring characteristic of plagiochiline N. Spectroscopic data of the synthetic product fully coincided with the reported data for the natural product.     

A stereoselective synthesis of (-)-tetrodotoxin

An asymmetric synthesis of the fugu fish poison, (-)-tetrodotoxin, is described. The route to this extraordinary target employs a number of unique transformations, foremost of which are two stereospecific C-H bond functionalization reactions. Accordingly, Rh-catalyzed carbene and nitrene C-H insertions facilitate rapid entry to the cyclohexane core of the natural product and make possible the late-stage installation of the tetrasubstituted carbinolamine center.     

Rapid Generation of Molecular Complexity by Chemical Synthesis: Highly Efficient Total Synthesis of Hexacyclic Alkaloid (−)‐Chaetominine and Its Biosynthetic Implications

The efficiency becomes a key issue in today's natural product total synthesis. While biomimetic synthesis is one of the most elegant strategies to achieve synthetic efficiency and thus to approach the ideal synthesis, most biogenetic pathways are unknown or unconfirmed. In this account, we demonstrate, through the shortest and also the most efficient asymmetric total syntheses of the hexacyclic alkaloid (?)‐chaetominine to date, that on the basis of biogenetic thinking, one can develop quite efficient bio‐inspired total synthesis, which in turn serves to suggest and chemically validate plausible biosynthetic routes for the natural product. The synthetic strategy thus developed is also inspiring for the development of other synthetic methods and efficient total synthesis of other natural products.     

Chemoenzymatic Synthesis of Cylindrocyclophanes A and F and Merocyclophanes A and D

Incorporating enzymatic reactions into natural product synthesis can significantly improve synthetic efficiency and selectivity. In contrast to the increasing applications of biocatalytic functional-group interconversions, the use of enzymatic C−C bond formation reactions in natural product synthesis is underexplored. Herein, we report a concise and efficient approach for the synthesis of [7.7]paracyclophane natural products, a family of polyketides with diverse biological activities. By using enzymatic Friedel–Crafts alkylation, cylindrocyclophanes A and F and merocyclophanes A and D were synthesized in six to eight steps in the longest linear sequence. This study demonstrates the power of combining enzymatic reactions with contemporary synthetic methodologies and provides opportunities for the structure–activity relationship studies of [7.7]paracyclophane natural products.     

Synthetic studies on the phorboxazoles: a short synthesis of an epi-C23 tetrahydropyran core

Studies on the synthesis of the anticancer natural products, the phorboxazoles have led to the synthesis of the C21-C32 penta-substituted tetrahydropyran core which is epimeric to the natural product at C23. The synthesis was achieved in only seven linear steps. The key steps were the use of a Masamune-Abiko anti-aldol reaction, the formation of a dihydropyran precursor molecule by the use of a new ‘Maitland-Japp-like’ cyclisation, and a highly diastereoselective reductive alkylation of the dihydropyran double bond, to generate the corresponding tetrahydropyran ring in an excellent yield.     

Rapid Access to Orthogonally Functionalized Naphthalenes: Application to the Total Synthesis of the Anticancer Agent Chartarin

We report the synthesis of orthogonally functionalized naphthalenes from simple, commercially available indanones in four steps. The developed method proceeds through a two‐step process that features a thermally induced fragmentation of a cyclopropane indanone with simultaneous 1,2‐chloride shift. Migration of the chloride substituent occurs in a regioselective manner to preferentially afford the para‐chloronaphthol substitution pattern. The obtained naphthols are versatile building blocks that can be selectively modified and used for the efficient construction of biologically active molecules. This has enabled the total synthesis of the potent anticancer natural product chartarin through a highly convergent retrosynthetic bond disconnection.     

Recent topics of the natural product synthesis by Horner–Wadsworth–Emmons reaction

The Horner–Wadsworth–Emmons (HWE) reaction has become well established among existing methodologies for the highly stereoselective olefination of carbonyl compounds. The reliability of this reaction in terms of its robustness, high stereoselectivity, and broad substrate scope permit retrosynthetic disconnection of the olefin bond in α,β-unsaturated carbonyl intermediates in natural product synthesis. This review discusses recent applications of the HWE reaction in natural product synthesis, highlighting its use for carbon chain elongation, coupling reactions of synthetic segments, ring-closing reactions, tandem reactions including HWE olefination, and asymmetric reactions.     

Enantioselective formal synthesis of antitumor agent (+)-ottelione A

The enantioselective formal synthesis of a natural antitumor product, (+)-ottelione A, was achieved through a catalytic enantioselective Diels-Alder strategy. These endeavors have led to the synthesis of a variety of synthetic analogues of this biologically potent natural product.     

C?H Bond Arylation in the Synthesis of Aryltetralin Lignans: A Short Total Synthesis of Podophyllotoxin

A short total synthesis of podophyllotoxin, the prototypical aryltetralin lignan natural product, is reported. Key to the success of this synthetic pathway is a Pd‐catalyzed C(sp³)–H arylation reaction enabled by a conformational biasing element to promote C–C reductive elimination over an alternative C N bond‐forming pathway. This strategy allows for access to the natural product in five steps from commercially available bromopiperonal, and sheds light on subtle conformational effects governing reductive elimination pathways from high‐valent palladium centers.     

CH Bond Arylation in the Synthesis of Aryltetralin Lignans: A Short Total Synthesis of Podophyllotoxin

A short total synthesis of podophyllotoxin, the prototypical aryltetralin lignan natural product, is reported. Key to the success of this synthetic pathway is a Pd‐catalyzed C(sp³)–H arylation reaction enabled by a conformational biasing element to promote C–C reductive elimination over an alternative C? N bond‐forming pathway. This strategy allows for access to the natural product in five steps from commercially available bromopiperonal, and sheds light on subtle conformational effects governing reductive elimination pathways from high‐valent palladium centers.     

Catalytic, enantioselective, vinylogous aldol reactions

In 1935, R. C. Fuson formulated the principle of vinylogy to explain how the influence of a functional group may be felt at a distant point in the molecule when this position is connected by conjugated double-bond linkages to the group. In polar reactions, this concept allows the extension of the electrophilic or nucleophilic character of a functional group through the pi system of a carbon-carbon double bond. This vinylogous extension has been applied to the aldol reaction by employing "extended" dienol ethers derived from gamma-enolizable alpha,beta-unsaturated carbonyl compounds. Since 1994, several methods for the catalytic, enantioselective, vinylogous aldol reaction have appeared, with which varying degrees of regio- (site), enantio-, and diastereoselectivity can be attained. In this Review, the current scope and limitations of this transformation, as well as its application in natural product synthesis, are discussed.