Intramolecular Suzuki-Miyaura Research Articles

Concise and Modular Chemoenzymatic Total Synthesis of Bisbenzylisoquinoline Alkaloids

The bisbenzylisoquinoline alkaloids (bisBIAs) have attracted tremendous attention from the synthetic community due to their diverse and intriguing biological activities. Herein, we report the convergent and modular chemoenzymatic syntheses of eight bisBIAs bearing various substitutes and linkages in 5‐7 steps. The gram‐scale synthesis of various well‐designed enantiopure benzylisoquinoline monomers was accomplished via an enzymatic stereoselective Pictet–Spengler reaction, followed by regioselective enzymatic methylation or chemical functionalizations in a sequential one‐pot process. A modified intermolecular copper‐mediated Ullmann coupling enabled the concise and efficient total synthesis of five different linear bisBIAs with either head‐to‐tail or tail‐to‐tail linkage. A biomimetic oxidative phenol dimerization selectively formed the sterically hindered, electron‐rich diaryl ether bond, and subsequent intramolecular Suzuki–Miyaura domino reaction or Ullmann coupling facilitated the first enantioselective total synthesis of three macrocyclic bisBIAs, including ent‐isogranjine, tetrandrine and O‐methylrepandine. This study highlights the great potential of chemoenzymatic strategies in the total synthesis of diverse bisBIAs and paves the way to further explore the biological functions of these natural products.

Inherently chiral nor-heteracalixarenes: design and synthesis via enantioselective intramolecular Suzuki-Miyaura reaction.

There has been a recent upsurge in research aimed at synthesizing inherently chiral molecules devoid of point, axial, planar and helical chiralities. We present herein our design and enantioselective synthesis of a series of inherently chiral macrocycles. These compounds, termed nor-heteracalixaromatics, feature a biaryl bond that replaces one of the aryl-heteroatom-aryl linkages found in classic heteracalix[4]aromatics. Macrocyclization of linear achiral substrates via an intramolecular Suzuki-Miyaura cross-coupling reaction affords the 15-membered cyclophane without any chiral elements in high yields and enantioselectivities. Notably, the formation of the aryl-aryl bond does not induce axial chirality at the biaryl linkage. Instead, it restricts the free rotation of an aromatic ring located four bonds away, leading to the inherent chirality of the macrocycle. The intriguing chiroptical properties of these compounds made them promising platform for the development of CPL emitters.

Solid-Phase Synthesis of Biaryl Cyclic Lipopeptides Derived from Arylomycins.

An efficient approach for the solid-phase synthesis of N-methylated tailed biaryl cyclic lipopeptides based on the structure of arylomycins was established. Each of these analogues incorporates an N-terminal linear lipopeptide attached to a biaryl cyclic tripeptide containing a Phe–Tyr, a Tyr–Tyr, or a His–Tyr linkage. This methodology first involved an intramolecular Suzuki–Miyaura arylation of a linear peptidyl resin incorporating the corresponding halogenated amino acid at the N-terminus and a boronotyrosine at the C-terminus. After N-methylation of the resulting biaryl cyclic peptidyl resin, the N-methylated lipopeptidyl tail was then assembled. The biaryl cyclic lipopeptides were purified and characterized.

Phenothiazine-Biaryl-Containing Fluorescent RGD Peptides.

Cyclic RGD peptides are well‐known ligands of integrins. The integrins αVβ3 and α5β1 are involved in angiogenesis, and integrin αVβ3 is abundantly present on cancer cells, thus representing a therapeutic target. Hence, synthetic and biophysical studies continuously are being directed towards the understanding of ligand‐integrin interaction. In this context, the development of versatile synthetic strategies to obtain fluorescent building blocks that can add molecular diversity and modular spectral characteristics while not compromising binding affinity or selectivity is a relevant task. An on‐resin intramolecular Suzuki–Miyaura cross‐coupling (SMC) between l‐ or d‐7‐bromotryptophan (7BrTrp) and a phenothiazine (Ptz) boronic acid affords fluorescent cyclic RGD pseudopeptides, c(RGD(W/w)Ptz). Ring closure by SMC establishes a phenothiazine–indole moiety with axial chirality. An array of eight novel compounds has been synthesized, among them one fluorescent compound with good affinity to integrin αVβ3. The fluorescence properties of the analogues can be efficiently tuned depending on the substituents in Ptz moiety even for fluorescence emission in the visible (red) spectral range.

Asymmetric Total Synthesis of Biphenylquinolizidine Alkaloids 4″-O-Demethyllythridine and 14-epi-4″-O-Demethyllythridine.

The first asymmetric total synthesis of new biphenylquinolizidine alkaloids 4″-O-demethyllythridine and 14-epi-4″-O-demethyllythridine isolated from Heimia salicifolia was accomplished. The key steps in the synthesis were a copper(I)-catalyzed asymmetric intramolecular aza-Michael reaction to build a chiral 4-arylquinolizidine unit and an intramolecular Suzuki-Miyaura cross-coupling reaction to construct a macrolactone ring comprising a biphenyl moiety.

An Operationally Simple and Mild Oxidative Homocoupling of Aryl Boronic Esters To Access Conformationally Constrained Macrocycles.

Constrained macrocyclic scaffolds are recognized as challenging synthetic motifs with few general macrocyclization methods capable of accessing these types of systems. Although palladium catalyzed oxidative homocoupling of aryl boronic acids and esters to biphenyls has been recognized as a common byproduct in Suzuki-Miyaura cross-couplings for decades, this reactivity has not been leveraged for the synthesis of challenging molecules. Here we report an oxidative boronic ester homocoupling reaction as a mild method for the synthesis of strained and conformationally restricted macrocycles. Higher yields and better efficiencies are observed for intramolecular diboronic ester homocouplings when directly compared to the analogous intramolecular Suzuki-Miyaura cross-couplings or reductive Yamamoto homocouplings. Substrates included strained polyphenylene macrocycles, strained cycloalkynes, and a key macrocyclic intermediate toward the synthesis of acerogenin A. Notably, this oxidative homocoupling reaction is performed at room temperature, open to atmosphere, and without the need to rigorously exclude water, thus representing an operationally simple alternative to traditional cross-coupling macrocyclizations. The mechanism of the reaction was investigated indicating that 1-5 nm palladium nanoparticles may serve as the active catalyst.

ChemInform Abstract: Amphoteric α‐Boryl Aldehyde Linchpins in the Synthesis of Heterocycles

AbstractReview: 56 refs.

Amphoteric α-Boryl Aldehyde Linchpins in the Synthesis of Heterocycles

Pairing of mutually reactive functional groups in the same molecule affords enabling opportunities in chemical synthesis. Kinetically amphoteric molecules exemplify this scenario and help avoid the pitfalls of protecting-group chemistry by exploiting the innate reactivity of the functional groups. In this perspective, we highlight the recent development of MIDA (N-methyliminodiacetyl) α-boryl aldehydes as amphoteric building blocks that act as linchpins in the synthesis of heterocycles. This short review includes topics ranging from metal-catalyzed cyclization involving B–C–Pd intermediates to the intramolecular Suzuki–Miyaura cross-coupling that affords six- and seven-membered rings. The use of boryl aldehydes in other transformations, including halogenation and oxidation protocols, is also discussed.

Synthesis of both enantiomers of the meta,meta-bridged diarylheptanoid Myricanol

The meta,meta-bridged diarylheptanoid myricanol isolated from the stem bark of Myrica cerifera is able to lower the levels of tau protein – a protein involved in the progression of Alzheimer's disease and several other neurodegenerative diseases. This biological activity, however, is highly dependent upon the stereochemistry of the sample. Here we report the synthesis of both enantiomers of myricanol. Pivotal to the success of this approach is the use of a remote stereocenter to influence the axial chirality of an aryl-aryl bond formed through an intramolecular Suzuki-Miyaura reaction.

Synthesis of Two Subunits of the Macrolide Domain of the Immunosuppressive Agent Sanglifehrin A and Assembly of a Macrolactone Precursor. Application of Masamune anti-Aldol Condensation

Asymmetric anti-aldol coupling of a norephedrine-derived ester with an α-chiral aldehyde was used to synthesize a carboxylic acid representing the C13-C19 segment of the macrocyclic domain present in the immunosuppressive agent sanglifehrin A. Felkin addition set configuration at the C14-C17 stereotetrad in this unit in which hydroxyl functions at C15 and C17 were masked as an internal ketal. The carboxyl group of this segment was coupled to the N-terminus of the tripeptide portion (C1-N12) of sanglifehrin A macrolactone to assemble the C1-C19 domain. Synthesis of the C20-C25 subunit of sanglifehrin A containing a (23S) alcohol was completed via asymmetric allylation of (E)-3-iodo-2-methylprop-2-enal followed by oxidative cleavage of the terminal vinyl appendage and a Takai olefination with pinacol dichloromethylboronate. Esterification of this alcohol with a C1-C19 carboxylic acid furnished an open C1-C25 macrolactone precursor, but this substance failed to undergo macrocyclization via intramolecular Suzuki-Miyaura coupling.

Total Synthesis of Bisbibenzyl Dibenzofuran Asterelin A via Intramolecular Oxidative Coupling

Total synthesis of asterelin A was accomplished by applying intramolecular Suzuki-Miyaura and oxidative couplings to the formation of an 18-membered macrocyclic ring and a dibenzofuran, respectively.

Total synthesis of riccardin C and (±)-cavicularin via Pd-catalyzed Ar–Ar cross couplings

Riccardin C, a specific LXRα agonist, is a representative macrocyclic bisbibenzyl-type natural product. As part of our synthetic studies on macrocyclic bisbibenzyls, the synthesis of riccardin C and its analog cavicularin was examined. The total synthesis of riccardin C was accomplished via a Pd-catalyzed intramolecular Suzuki–Miyaura coupling as the key macrocyclization step. This synthetic strategy was also extended in the synthesis of (±)-cavicularin, which was then attained by constructing the dihydrophenanthrene moiety using a Pd-catalyzed Ar–Ar coupling reaction.

Enantioselective Syntheses of Tetrahydroquinolines Based on Iridium‐Catalyzed Allylic Substitutions: Total Syntheses of (+)‐Angustureine and (–)‐Cuspareine

AbstractA protecting‐group‐free two‐step approach for the preparation of tetrahydroquinolines has been developed. The procedure involves a highly regio‐ and enantioselective intermolecular iridium‐catalyzed allylic amination followed by one‐pot hydroboration and intramolecular Suzuki–Miyaura cross‐coupling. This method was applied in total syntheses of the alkaloids (+)‐angustureine and (–)‐cuspareine.

Solid-phase synthesis of biaryl cyclic peptides by borylation and microwave-assisted intramolecular Suzuki–Miyaura reaction

Miyaura borylation and Suzuki–Miyaura cross-coupling have been combined to set up an efficient strategy for the solid-phase synthesis of biaryl cyclic peptides. The Miyaura borylation was the key step in obtaining the linear peptidyl resin precursor containing both the boronate and the halogenated derivative of an aromatic amino acid. The Suzuki–Miyaura macrocyclization was performed under microwave irradiation leading to biaryl cyclic peptides of different ring sizes.

Intramolecular Suzuki–Miyaura Reaction for the Total Synthesis of Signal Peptidase Inhibitors, Arylomycins A2 and B2

Development of the total syntheses of arylomycins A(1) and B(2) is detailed. Key features of our approach include 1) formation of 14-membered meta,meta-cyclophane by an intramolecular Suzuki-Miyaura reaction; 2) incorporation of N-Me-4-hydroxyphenylglycine into the cyclization precursor, which avoids the late-stage low-yielding N-methylation step; 3) segment coupling of a fully elaborated peptide side chain to the macrocycle, which makes the synthesis highly convergent. Overall, arylomycin A(2) was obtained in 13 steps from L-Tyr for the longest linear sequence, in 13 % overall yield. Arylomycin B(2) was synthesized in 10 steps from L-3-nitro-Tyr, in 10 % overall yield.

Synthesis of riccardin C and its seven analogues. Part 1: The role of their phenolic hydroxy groups as LXRα agonists

Riccardin C, a nuclear receptor LXRα selective agonist, is an 18-membered macrocyclic bisbibenzyl isolated from several liverworts. Synthesis of riccardin C and its seven O-methylated derivatives was accomplished. The synthetic sequence highlights an intramolecular Suzuki–Miyaura coupling in the formation of the 18-membered biaryl linkage present in riccardin C. The structure–activity relationship of these compounds suggests that all of the phenolic hydroxy groups present in riccardin C are essential for the activation of LXRα.

Total Synthesis of Arylomycin A2, a Signal Peptidase I (SPase I) Inhibitor

A concise total synthesis of arylomycin A2 has been accomplished featuring a key intramolecular Suzuki-Miyaura reaction for the formation of the 14-membered meta,meta-cyclophane and direct coupling of a fully elaborated peptide side chain with the macrocyclic core.

Synthesis of DEFG Ring of Complestatin and Chloropeptin I: Highly Atropdiastereoselective Macrocyclization by Intramolecular Suzuki-Miyaura Reaction

Palladium-catalyzed intramolecular Suzuki-Miyaura reaction of linear tripeptide (23) afforded the 16-membered DEFG ring of complestatin (3) in good yield with an excellent atropdiastereoselectivity. Acidic treatment of 3 triggers a stereospecific rearrangement leading to the corresponding DEFG ring 4 of chloropeptin I.

Microwave‐Assisted Intramolecular Suzuki—Miyaura Reaction to a Macrocycle: Concise Asymmetric Total Synthesis of Biphenomycin B.

Microwave‐Assisted Intramolecular Suzuki—Miyaura Reaction to a Macrocycle: Concise Asymmetric Total Synthesis of Biphenomycin B.

Microwave-Assisted Intramolecular Suzuki−Miyaura Reaction to Macrocycle, a Concise Asymmetric Total Synthesis of Biphenomycin B

[reaction: see text] A concise and efficient total synthesis of biphenomycin B has been accomplished featuring a key microwave-assisted intramolecular Suzuki-Miyaura reaction for formation of the 15-membered meta,meta-cyclophane 20.