Divergent Asymmetric Total Syntheses of (-)-Alloaristoteline and (+)-Aristoteline via Directed Indolization Strategies.

A divergent asymmetric synthetic route to (-)-alloaristoteline and (+)-aristoteline is described. The key doubly bridged tricyclic enol triflate common intermediate prepared via enantioselective deprotonation and stepwise annulation was successfully bifurcated to complete the first completely synthetic construction of the titled natural alkaloids upon strategic implementation of the late-state directed indolization methods.

A Regio- and Diastereoselective Stille Coupling/Intramolecular Diels-Alder Cascade for the Generation of Fused Pyridines and Application in the Synthesis of (+)-Lycopladine A and (-)-Lycoposerramine R.

2-Pyrones with a chiral branched allylic silyl ether substituent underwent intramolecular Diels-Alder reactions with remarkably high π-facial- and endo-selectivities. The resulting diastereomerically and enantiomerically pure cycloadducts were transformed into the natural products (+)-lycopladine A and (-)-lycoposerramine R.

Asymmetric Divergent Total Syntheses of (+)-Decursivine and (+)- Serotobenine via Intramolecular Fischer Indole Synthesis.

A new asymmetric synthetic route to (+)-decursivine and (+)-serotobenine is formulated. The key developments are the de novo construction of the crucial eight-membered 3,4-fused tricyclic indole ring engaged by the intramolecular Fischer indole synthesis and the stereocontrolled assembly of the dihydrobenzofuran subunit mediated by the asymmetric intramolecular Rh-carbenoid C-H insertion. BF3-mediated selective C15 epimerization followed by removal of the amine masking groups completed the target natural compounds' asymmetric and divergent total syntheses.

Transition-metal-catalyzed ortho-selective C-H functionalization reactions of free phenols.

Phenols are important readily available chemical feedstocks and versatile synthetic building blocks for diverse synthetic transformations. Their motifs are prevalent in a diverse array of natural products, pharmaceuticals, functional materials, and privileged chiral ligands. Consequently, the development of facile and direct site-selective C-H bond functionalization of free phenols is of great importance and considerable interest to both industry and academic research. Over the past decades, transition-metal-catalyzed C-H bond functionalization has become as a powerful synthetic tool in organic synthesis. In this review, we provide a brief overview of recent progress in the transition-metal-catalyzed direct ortho-selective C-H functionalization of free phenols.

A Stereodivergent Strategy for Total Syntheses of Antirhine Alkaloids.

Total syntheses of the antirhine alkaloids are described. The cyanide-catalyzed imino-Stetter reaction of the aldimine derived from ethyl 2-aminocinnamate and 4-bromopyridine-2-carboxaldehyde provided a 2-pyridinyl substituted indole-3-acetate, which was further converted into the corresponding indoloquinolizidinium intermediate through C-ring formation. Subsequent trans-selective installation of the homoallylic alcohol side-chain at C-15 in the resulting indoloquinolizidinium allowed the total syntheses of antirhine and its known epimer.

Imidazole-Selective Alkyne Hydroamination under Physiological Conditions.

Imidazole-selective intermolecular hydroamination reaction has been discovered. This unprecedented additive-free addition reaction proceeds in an exclusively regioselective and stereoselective manner with high atom economy under extremely mild reaction conditions.

Total Synthesis of (±)-Clivonine via Diels-Alder Reactions of 3,5-Dibromo-2-pyrone.

New synthetic routes to (±)-clivonine were devised starting with the Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone with styrene pinacol boronate dienophiles. In the first-generation synthesis, the pivotal perhydroindoline system including the C5-hydroxyl group was constructed via a reaction sequence involving the Eschenmoser-Claisen rearrangement and regio/stereoselective epoxide opening reaction. In the second-generation synthesis, a radical-mediated cyclization approach was employed for the rapid assembly of the pyrrolidine ring. In this route, the C5-hydroxyl group provided by the dienophile in a stereochemically defined form was preserved throughout the synthesis.

Aminooxygenation of Ynamides with N-Hydroxybenzotriazoles: Synthesis of α-Benzotriazolyl Carbonyl Compounds.

Addition of N-hydroxybenzotriazoles to ynamides causes spontaneous rearrangement, resulting in α-benzotriazolyl imides. The transformation proceeded at rt in the absence of any catalyst but could be efficiently catalyzed by Zn(OTf)2. Crossover experiments confirmed that the rearrangement is an intramolecular process, most likely via a concerted mechanism. However, heating the mixture above 110 °C resulted in isomerization of N2 into N1 product, via heterolytic C-N bond dissociation. This tandem addition-rearrangement sequence provides an efficient and atom-economical synthetic route for the synthesis of α-benzotriazolyl carbonyl compounds.

New Synthetic Routes to (+)-Uleine and (-)-Tubifolidine: General Approach to 2-Azabicyclo[3.3.1]nonane Indole Alkaloids.

Novel asymmetric synthetic routes to (+)-uleine and (-)-tubifolidine are reported herein. The regioselective formation of enol triflates from 2-azabicyclo[3.3.1]nonane ketones followed by indolizations of the resultant ene-hydrazides allowed the efficient construction of key indole intermediates, facilitating the total synthesis of the target natural alkaloids.

General Strategy for the Synthesis of Antirhine Alkaloids: Divergent Total Syntheses of (±)-Antirhine, (±)-18,19-Dihydroantirhine, and Their 20-Epimers.

A general synthetic strategy for antirhine alkaloids was developed in this study. The cyanide-catalyzed imino-Stetter reaction of ethyl 2-aminocinnamate and 4-bromopyridine-2-carboxaldehyde afforded the corresponding indole-3-acetic acid derivative. Subsequent formation of the six-membered C ring followed by trans-selective installation of the two-carbon unit at C-15 provided rapid access to the key intermediate. Stereoselective installation of substituents at C-20 allowed the total syntheses of (±)-antirhine, (±)-18,19-dihydroantirhine, and their 20-epimers, all of the known natural products in the antirhine family.

Transforming Oxadiazolines through Nitrene Intermediates by Energy Transfer Catalysis: Access to Sulfoximines and Benzimidazoles.

Subtle differences in reaction conditions facilitated unprecedented photocatalytic reactions of oxadiazolines by energy transfer catalysis. A set of compounds, sulfoximines and benzimidazoles, were ingeniously prepared from oxadiazolines via nitrene intermediates by photocatalytic N-O/C-N bond cleavages. The synthesis of sulfoximines was realized through intermolecular N-S bond formation between nitrene intermediates and sulfoxides, whereas benzimidazoles were obtained via intramolecular aromatic substitution of the nitrene to the tethered aryl substituent.

H-Bonding Mediated Asymmetric Intramolecular Diels-Alder Reaction in the Formal Synthesis of (+)-Aplykurodinone-1.

An asymmetric formal total synthesis of (+)-aplykurodinone-1 was achieved using a route, in which hydrogen bonding serves as a stereochemical control element governing the π-facial selectivity of intramolecular Diels-Alder (IMDA) reaction of an enone tethered 2-pyrone. In the IMDA process, the configuration at a stereogenic, hydroxyl bearing an α-carbon in the enone dienophile is conveyed in a highly effective manner through intramolecular hydrogen bonding with the enone carbonyl oxygen. The tricyclic lactone, generated in this process, was successfully converted to a late stage intermediate in Danishefsky's synthesis of aplykurodinone-1.

Total Syntheses of Lobaric Acid and Its Derivatives from the Antarctic Lichen Stereocaulon alpinum.

The first total syntheses of the natural products lobaric acid (1) and its derivatives isolated from the Antarctic lichen Stereocaulon alpinum are reported in this study. Lobarin (3), with a pseudodepsidone structure, was synthesized first in 11 steps by utilizing an Ullmann aryl ether coupling reaction, and lobaric acid was synthesized in an additional three steps by a seven-membered lactonization reaction. Various derivatives were also obtained from the prepared lobaric acid, and the synthetic compounds exhibited significant PTP1B inhibitory activities.

Directed Fischer Indolization as an Approach to the Total Syntheses of (+)-Aspidospermidine and (-)-Tabersonine.

A conceptually new synthetic approach that provides general access to the aspidosperma alkaloids (+)-aspidospermidine and (-)-tabersonine was developed. This method is based on the regioselective indolization of an ene-hydrazide, which was obtained via a base-catalyzed intramolecular aza-Michael reaction, in situ trapping of the resulting enolate, and subsequent C-N coupling with phenyl hydrazide.

Total Syntheses of Ningalins D and G.

A flexible synthetic strategy for the total syntheses of ningalins D and G is described. The highly effective TMS-OTf/2,6-lutidine-mediated [3,3]-sigmatropic rearrangement of densely loaded dinaphthyl hydrazides and cyclization of the resulting 2,2'-diamino-1,1'-dinaphthyls afforded the key 7H-dibenzo[c,g]carbazole intermediates. Successful conversions to biphenylene quinone methides followed by regioselective brominations completed the total syntheses of the titled marine alkaloids.

Visible-Light-Induced Synthesis of Carbazoles by in Situ Formation of Photosensitizing Intermediate.

A visible-light-induced synthesis of N-H carbazoles from easily accessible 2,2'-diaminobiaryls in the absence of any external photosensitizer is reported. The process only requires tBuONO and natural resources, visible light, and molecular oxygen for the synthesis of N-H carbazoles. Experimental and computational studies support that the in situ formation of a visible-light-absorbing photosensitizing intermediate, benzocinnoline N-imide, is responsible for the activation of triplet molecular oxygen to singlet oxygen that, in turn, promotes the synthesis of carbazole.

Intramolecular Fischer Indole Synthesis for the Direct Synthesis of 3,4-Fused Tricyclic Indole and Application to the Total Synthesis of (-)-Aurantioclavine.

Aryl hydrazides with a ketone or aldehyde containing side chains linked to the meta-position of the aromatic ring undergo acid-promoted intramolecular Fischer indole synthesis to generate 3,4-fused tricyclic indoles. The preparative utility of this conceptually new synthetic approach, which does not require prefunctionalization of the indole ring, was demonstrated by its application to a concise total synthesis of (-)-aurantioclavine.

Total Synthesis of (-)-Neocosmosin A via Intramolecular Diels-Alder Reaction of 2-Pyrone.

A new synthetic route to (-)-neocosmosin A was devised by elaboration of intramolecular Diels-Alder (IMDA) cycloaddition of 2-pyrone containing a bromopropiolate group as the dienophile. The IMDA reaction was accompanied by cycloreversion of carbon dioxide to give benzannulated macrolide with two bromide groups at C14 and C16. Installation of the pinacolboryl groups and oxidations allowed completion of the total synthesis of (-)-neocosmosin A.

Total synthesis of (±)-lycorine from the endo-cycloadduct of 3,5-dibromo-2-pyrone and (E)-ß-borylstyrene.

A new synthetic route to (±)-lycorine, starting from the endo-cycloadduct of 3,5-dibromo-2-pyrone and (E)-ß-borylstyrene, is reported. Boronate oxidation and a set of reactions including face-selective epoxidation provided the pivotal C1-OH group and C3/C3a double bond.

Ene-hydrazide from enol triflate for the regioselective Fischer indole synthesis.

Ene-hydrazide prepared from enol triflate undergoes a Fischer indolization reaction to give the corresponding indole with complete regioselectivity. The starting enol triflate is readily accessed in regiochemically defined form from the ketone precursor via various well-established methods. This new protocol was successfully applied to the synthesis of desbromoarborescidine A, a natural ß-carboline alkaloid, difficult to prepare with conventional Fischer indole synthesis.