Total synthesis of the 7,3'-linked naphthylisoquinoline alkaloid ancistrocladidine

The first total synthesis of ancistrocladidine, a rare 7,3'-linked naphthylisoquinoline alkaloid, has been completed, with the key feature of the synthesis being the formation of the extremely hindered biaryl linkage by ortho-arylation of a naphthol with an aryllead triacetate. Initial efforts were focused on the generation of a heteroaryl lead species, which would have allowed a convergent synthesis to be developed. However, it was not possible to generate such a lead species. A simpler aryl lead triacetate was prepared and reacted. The resulting biaryl aldehyde was elaborated in 10 steps to form a 1:1 mixture of ancistrocladidine and its atropisomer. Recrystallization of the mixture afforded ancistrocladidine, which was identical in all respects to the reported data.     

First Atroposelective Total Synthesis of Enantiomerically Pure Ancistrocladidine and Ancistrotectorine

The first regio‐ and stereoselective total synthesis of the axially chiral 7,3′‐coupled naphthylisoquinoline alkaloids ancistrocladidine ( 1 ) and ancistrotectorine ( 2 ) has been described. Both possess a 7,3′‐coupled axis, which before now, was difficult to attain synthetically. Moreover, target 2 has a sensitive relative cis‐array of the two methyl groups at C1 and C3 in the tetrahydroisoquinoline part. The key step in the chosen strategy was the construction of the biaryl axis in accordance with the “lactone method”: the two molecular halves, which were activated in an “inverse‐halogenated” form, were prefixed by an ester bridge, followed by intramolecular coupling, and atroposelective cleavage of the lactone auxiliary bridge delivered the desired biaryl scaffold.     

Palladium‐Catalyzed,tert‐Butyllithium‐Mediated Dimerization of Aryl Halides and Its Application in the Atropselective Total Synthesis of Mastigophorene A

A palladium‐catalyzed direct synthesis of symmetric biaryl compounds from aryl halides in the presence of tBuLi is described. In situ lithium–halogen exchange generates the corresponding aryl lithium reagent, which undergoes a homocoupling reaction with a second molecule of the aryl halide in the presence of the palladium catalyst (1 mol %). The reaction takes place at room temperature, is fast (1 h), and affords the corresponding biaryl compounds in good to excellent yields. The application of the method is demonstrated in an efficient asymmetric total synthesis of mastigophorene A. The chiral biaryl axis is constructed with an atropselectivity of 9:1 owing to catalyst‐induced remote point‐to‐axial chirality transfer.     

Palladium‐Catalyzed,tert‐Butyllithium‐Mediated Dimerization of Aryl Halides and Its Application in the Atropselective Total Synthesis of Mastigophorene A

A palladium‐catalyzed direct synthesis of symmetric biaryl compounds from aryl halides in the presence of tBuLi is described. In situ lithium–halogen exchange generates the corresponding aryl lithium reagent, which undergoes a homocoupling reaction with a second molecule of the aryl halide in the presence of the palladium catalyst (1 mol %). The reaction takes place at room temperature, is fast (1 h), and affords the corresponding biaryl compounds in good to excellent yields. The application of the method is demonstrated in an efficient asymmetric total synthesis of mastigophorene A. The chiral biaryl axis is constructed with an atropselectivity of 9:1 owing to catalyst‐induced remote point‐to‐axial chirality transfer.     

Tetralones as precursors for the synthesis of 2,2′-disubstituted 1,1′-binaphthyls and related compounds

Using tetralones as starting materials, the synthesis of biaryl compounds is described in this paper. The tetralones were initially converted into 1-bromo-3,4-dihydro-2-naphthalenecarbaldehydes before effecting aromatization into the corresponding naphthalenes. These products were then subjected to Suzuki-Miyaura cross-coupling reactions, with a variety of aromatic boronic acids containing substituents in the ortho position, to afford biaryl compounds. The biaryl compounds possess heteroatom containing substituents ortho to the newly formed biaryl axis.     

Applications of vinylogous Mannich reactions. Total syntheses of the Ergot alkaloids rugulovasines A and B and setoclavine.

Concise syntheses of the Ergot alkaloids rugulovasine A (3a), rugulovasine B (3b), and setoclavine (2) have been completed by strategies that feature inter- and intramolecular vinylogous Mannich reactions as the key steps. Thus, the first synthesis of 3a,b commenced with the conversion of the known indole 17 into 24 via the addition of the furan 22 to the iminium ion 21, which was generated in situ from the aldehyde 19. Cyclization of 24 by a novel S(RN)1 reaction followed by removal of the N-benzyl group furnished a mixture (1:2) of 3a and 3b. In an alternative approach to these alkaloids, the biaryl 35 was reduced with DIBAL-H to give an intermediate imine that underwent spontaneous cyclization via an intramolecular vinylogous Mannich addition to provide 36a,b. N-Methylation of the derived benzyl carbamates 37a,b followed by global deprotection gave a mixture (2:1) of rugulovasines A and B (3a,b). Setoclavine (2) was then prepared from the biaryl 41 using a closely related intramolecular vinylogous Mannich reaction to furnish the spirocyclic lactones 42a,b. These lactones were subsequently transformed by hydride reduction and reductive methylation into the ergoline derivatives 43a,b, which were in turn converted into 2 by deprotection and solvolytic 1,3-rearrangement of the allylic hydroxyl group.     

Enantioselective total synthesis of parnafungin A1 and 10a-epi-hirtusneanine

The first and enantioselective total synthesis of the heterodimeric biaryl antifungal natural product parnafungin A1 as well as complex biaryl tetrahydroxanthone 10a-epi-hirtusneanine is accomplished, by employing cross-coupling through the benzoxaborole strategy to construct their sterically hindered biaryl cores. Besides the powerful Suzuki–Miyaura cross-coupling, the synthesis of parnafungin A1 also features a highly diastereoselective oxa-Michael addition to construct a tetrahydroxanthone skeleton, and an effective Zn-mediated reductive cyclization-Mitsunobu sequence to furnish the isoxazolidinone structure. Key innovations in total synthesis of 10a-epi-hirtusneanine include the employment of DTBS protection for functional group manipulation on the tetrahydroxanthone skeleton, stereoselective methylations, and complete reversal of the stereochemistry of the C5-hydroxy group using oxidation/Evans–Saksena reduction, as well as the strategy of preparing both complex tetrahydroxanthone monomers from the same chiral intermediate 25.

The first, enantioselective total synthesis of the heterodimeric biaryl antifungal natural product parnafungin A1 as well as 10a-epi-hirtusneanine is accomplished, using a cross-coupling strategy to construct their sterically hindered biaryl cores.     

Synthesis of Axially Chiral Biaryl‐2‐amines by PdII‐Catalyzed Free‐Amine‐Directed Atroposelective C−H Olefination

A simple and ubiquitously present group, free amine, is used as a directing group to synthesize axially chiral biaryl compounds by Pd^II‐catalyzed atroposelective C?H olefination. A broad range of axially chiral biaryl‐2‐amines can be obtained in good yields with high enantioselectivities (up to 97 % ee). Chiral spiro phosphoric acid (SPA) proved to be an efficient ligand and the loading could be reduced to 1 mol % without erosion of enantiocontrol in gram‐scale synthesis. The resulting axially chiral biaryl‐2‐amines also provide a platform for the synthesis of a set of chiral ligands.     

Convergent Synthesis of Naphthylisoquinoline Alkaloids: Total Synthesis of (+)-O-Methylancistrocline

A highly convergent synthesis of the methyl ether derivative 2a of the naphthylisoquinoline alkaloid ancistrocline (2) is described. The key step involves a stereoselective biaryl coupling between the chiral oxazoline 3 and the Grignard reagent 4 derived from the optically active tetrahydroisoquinoline 8. The atropisomeric mixture was then converted to the separable acetamides 11 and 12, which were obtained in a ratio of 16:84 and an overall yield of 32% for the three steps. The major atropisomer 12 was then converted into O-methylancistrocline (2a), which was identical to a semisynthetic sample derived from the related alkaloid ancistrocladinine (14).     

Solid-phase synthesis of biaryl cyclic peptides containing a histidine-tyrosine linkage

A solid-phase strategy for the synthesis of biaryl cyclic peptides containing a side-chain to side-chain His-Tyr linkage was developed. The key step was the macrocyclization of a linear peptidyl resin incorporating a 5-bromohistidine and a 3-boronotyrosine via the formation of the biaryl bond by means of a microwave-assisted Suzuki-Miyaura reaction. This method allowed direct access to biaryl cyclic peptides containing a 3- or 5-amino acid ring and bearing the histidine residue at the N- or the C-terminus, being especially conducive for analogues in which this amino acid is located at the C-terminus. This study also served to establish a strategy for the synthesis of biaryl cyclic peptides derived from the two hemispheres of the natural biaryl bicyclic peptides aciculitins.     

Synthesis of cribrostatin 6

The synthesis of cribrostatin 6 (1) is described. A regioselective bromination, a biaryl coupling, and an intramolecular cyclization are the key steps in the synthesis.     

Stereochemistry of isoplagiochin C, a macrocyclic bisbibenzyl from liverworts

Cyclic bisbibenzyls, like isoplagiochins C (1) and D (2), are stereochemically intriguing molecules: Although not equipped with any of the traditional stereogenic elements that render molecules conformationally stable per se, they are sometimes isolated in an optically active form and are thus chiral at room temperature. The paper describes quantum chemical calculations, in particular investigations of the conformational space and molecular dynamics simulations, showing that the helicity is a property of the entire molecule, whose ring strain makes the molecule configurationally stable overall, with (formally) three stereogenic elements (two biaryl axes and one helical stilbene unit). Only one of the biaryl axes (the 'upper' one, joining C-12' and C-14) has a stable configuration, leading to a population of four interconverting diastereomers, yet without racemization at room temperature. On the basis of these conformational and dynamic calculations, the circular dichroism spectrum of isoplagiochin C (1) was calculated, leading to the first assignment of the absolute configuration of a cyclic bisbibenzyl. Accordingly, 1 has the P-configuration at the stereochemically stable biaryl axis and constitutes a mixture of diastereomers with respect to the other biaryl axis and the helical stilbene unit. From the temperature dependence of the racemization rates, an enantiomerization barrier of 101.6 kJ/mol was determined. Likewise, for the first time for cyclic bisbibenzyls, the enantiomeric ratio of this natural product was determined, by chromatography on a chiral phase with CD-coupling. Accordingly, 1 from Plagiochila deflexa is not enantiomerically pure, but occurs in a 85:15 ratio in favor of the enantiomer that has the P-configuration at the stereochemically stable axis.     

Progress toward synthesis of diazonamide A. Preparation of a 3-(oxazol-5-yl)-4-trifluoromethyl-sulfonyloxyindole and its use in biaryl coupling reactions

[formula: see text] The synthesis of a 3-oxazol-5-yl-indole-4-triflate is described, featuring a Sch?lkopf reaction to prepare the oxazole. In addition, the participation of this intermediate in biaryl coupling reactions toward the total synthesis of the natural product diazonamide A is presented.     

Diels-Alder approach for the construction of halogenated, o-nitro biaryl templates and application to the total synthesis of the anti-HIV agent siamenol

A rapid Diels-Alder approach to halogenated biaryl templates is described. These biaryl templates are available in two steps from the corresponding aromatic aldehydes. The scope of subsequent Suzuki couplings on the biaryl chlorides is explored. Good tolerance for both electron-donating and electron-withdrawing groups in the coupling process can be achieved. Further functionalization of the biaryl templates is described. Hydrogenation of the nitro moiety with concomitant removal of the benzyl ether yields the o-anilino, o-phenolic polyaryls. Selective reduction of the nitro group can be accomplished. Alternatively, the benzyl ether can be selectively removed under Lewis acidic conditions. The utilization of the Diels-Alder adducts for the synthesis of a series of chlorinated carbazoles via the Cadogan cyclization is also demonstrated. Finally, application of this technology to the total synthesis of siamenol, an anti-HIV agent, is reported.     

The Directed Synthesis of Biaryl Compounds: Modern Concepts and Strategies

The preparation and utilization of specific biaryl systems, particularly those which suffer hindered rotation, is a demanding goal not only in the synthesis of natural products and Pharmaceuticals, but also for example in the discovery of new reagents for asymmetric synthesis. This article will attempt to provide a topical review of modern, efficient processes for the specific preparation of biaryls. This appears to be of particular urgency, since, under the pressure of continually increasing demand, a wealth of new or modified synthetic approaches to the ever more important biaryl systems has been realized in recent years. The high standard which has been reached in this field is impressively demonstrated by regio- and stereoselective syntheses of important biaryl natural products such as steganone, ancistrocladine, ancistrocladisine, and dioncophylline A. Besides the utilization of asymmetric induction in the actual coupling step, the thermodynamically or kinetically controlled torsion of biaryl axes belongs to the most important concepts discussed.     

Enantioselective synthesis of the dimeric pyranonaphthoquinone core of the cardinalins using a late-stage homocoupling strategy

The enantioselective synthesis of a dimeric pyranonaphthoquinone closely related to the cardinalins is described. Whilst attempts to effect a double Hauser-Kraus annulation of enone 5 were unsuccessful using both bis-phthalide 4 and bis-sulfone 21, a single annulation of cyanophthalide 28 with enone 5 furnished functionalised naphthalene 31. Suzuki-Miyaura homocoupling of the aryl triflate 29 derived from 31 effected a late-stage construction of the biaryl bond and facilitated access to the biaryl 3. Double stereoselective lactol reduction installed the 1,3-cis stereochemistry of the pyran rings and a final double oxidative demethylation step furnished model dimer 1, completing the enantioselective synthesis of a dimeric pyranonaphthoquinone bearing the core structure of cardinalin 3.     

Heck, direct arylation, and hydrogenation: two or three sequential reactions from a single catalyst

Palladium-catalyzed tandem multifunctional reactions leading to the synthesis of substituted biaryl molecules have been developed including tandem Heck-direct arylation and tandem-sequential Heck-direct arylation-hydrogenation. These reactions occur in good yield and have been employed in the synthesis of a cytotoxic biaryl compound.     

Efficient synthesis of substituted biaryl anilines and biaryl phenols via a Suzuki cross-coupling reaction

An efficient synthesis of biaryl building blocks with multiple point diversities via a Suzuki cross-coupling reaction using a commercially available preformed Pd catalyst 1 was reported. Substituted biaryl anilines and phenols were obtained in one step from commercially available aryl halides.     

Diels-Alder approach to biaryls: elucidation of competing tandem [2+2] cycloaddition/[1,3] sigmatropic shift pathway

Reaction of 2-halo-6-nitrophenylacetylene with an electron deficient diene gives rise to a [4+2] cycloaddition/cycloreversion biaryl product and a bicyclo[4.2.0]octadiene resulting from a competing [2+2] cycloaddition pathway. The cyclobutene can be opened to give a mixture of cyclooctatriene and biaryl in varying amounts depending on heat and light exposure. The conversion of the cyclobutene into biaryl occurs through a [1,3] sigmatropic carbon shift followed by [4+2] cycloextrusion of ethylene gas.     

Synthesis of symmetrical biaryl compounds by homocoupling reaction

Since the development of the Ullmann coupling in the early 20th Century, there has been intense and continuous research on the syntheses of biaryl compounds, which appears as an interesting branch of organic chemistry.A myriad of methodologies for the synthesis of biaryl compounds have been studied and well established, including homocoupling methodologies, which in general are robust as well as consolidated strategies. Biaryl systems are quite relevant building blocks for the synthesis of more complex chemical structures. Besides the diversity of functional groups that can be used to promote a new aryl-aryl bond, there is a wide variety of transition metals that can act as catalyst in these processes.In this review, we summarized numerous methodologies of homocoupling reactions for the synthesis of symmetrical biaryl compounds.