Acyl Rearrangement Research Articles

Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol

Taxol is a widely-applied anticancer drug that inhibits microtubule dynamics in actively replicating cells. Although a minimum 19-step biosynthetic pathway has been proposed and 16 enzymes likely involved have been characterized, stepwise biosynthetic reactions from the well-characterized di-oxygenated taxoids to Taxol tetracyclic core skeleton are yet to be elucidated. Here, we uncover the biosynthetic pathways for a few tri-oxygenated taxoids via confirming the critical reaction order of the second and third hydroxylation steps, unearth a taxoid 9α-hydroxylase catalyzing the fourth hydroxylation, and identify CYP725A55 catalyzing the oxetane ester formation via a cascade oxidation-concerted acyl rearrangement mechanism. After identifying a acetyltransferase catalyzing the formation of C7-OAc, the pathway producing the highly-oxygenated 1β-dehydroxybaccatin VI with the Taxol tetracyclic core skeleton is elucidated and its complete biosynthesis from taxa-4(20),11(12)-diene-5α-ol is achieved in an engineered yeast. These systematic studies lay the foundation for the complete elucidation of the biosynthetic pathway of Taxol.

Development of Dynamically Chiral Helical Polymer Catalysts Based on Post-Polymerization Modification of Boronyl Pendants

Catalytic asymmetric synthesis is one of the most efficient methods for the preparation of chiral compounds with high optical purity. Although a variety of robust chiral scaffolds have been developed to achieve efficient chiral catalysts which show high catalytic activities and stereoselectivities, use of dynamic chiral scaffold is desired for the development of advanced chiral catalysts featuring stimuli-responsive properties such as chirality-switching and asymmetric amplification. We have developed chirality-switchable helical polymer ligands bearing monodentate phosphine pendants, which exhibit high enantioselectivities based on solvent-dependent dynamic screw-sense control of poly(quinoxaline-2,3-diyl)s (PQXs) having chiral side chains. However, the application has been limited to palladium-catalyzed asymmetric reactions. This article describes the development of helically chiral polymer catalysts based on post-polymerization modification of bornyl pendants (-B(OH)2) attached to the PQXs. Introduction of 2,2′-bipyridine pendants to chiral PQXs through Suzuki-Miyaura coupling at the boronyl pendants led to the development of chirality-switchable helical polymer ligands for copper-catalyzed asymmetric reactions. In addition, introduction of 4-aminopyridine pendants into the chiral PQXs provided chirality-switchable efficient asymmetric nucleophilic catalysts for kinetic resolution of secondary alcohols and asymmetric Steglich-type acyl rearrangements. Furthermore, by using the boronyl pendants as molecular recognition sites for screw-sense induction to achiral PQXs, a chiral-guest-responsive helical polymer ligand bearing monodentate phosphine pendants was developed for the palladium-catalyzed asymmetric reaction. Using an amino alcohol as a chiral additive, the screw-sense induction proceeded with asymmetric amplification, giving the corresponding product with higher optical purity than that of the chiral additive.

Rhodium-Catalyzed N-Arylation of 2-Pyridones Enabled by 1,6-Acyl Migratory Rearrangement of 2-Oxypyridines

An efficient rhodium-catalyzed dearomative rearrangement of 2-oxypyridines with quinone diazides has been developed for the direct synthesis of N-arylated pyridones, in which a novel 1,6-O-to-O rather than 1,4-O-to-C acyl rearrangement has been achieved under mild reaction conditions.

Difluorocarbene-Triggered Acyl Rearrangement Reaction: A Strategy for the Direct Introduction of the gem-Difluoromethylene Group.

A novel metal- and catalyst-free dearomative reaction of 2-oxypyridines to construct gem-difluoromethylenated N-substituted 2-pyridones has been developed. The reaction involves an attractive acyl rearrangement from O to CF2 of difluorocarbene-derived pyridinium ylides, which provides a new strategy for the direct introduction of the gem-difluoromethylene group with high efficiency and selectivity as well as broad substrate scope. Gram-scale synthesis and synthetic transformations have also been demonstrated.

Rhodium-Catalyzed Formal C═O Bond Insertion and Sequential Acyl 1,4-N-to-O Migratory Rearrangement.

We present here a rhodium-catalyzed reaction between N-acyl pyridazinones and diazoacetates, leading to pyridazine derivatives in good yield under mild reaction conditions. This whole sequence probably proceeds through a carbene insertion into a C═O bond and an unprecedented 1,4-N-to-O acyl rearrangement reaction.

Modular and stereoselective synthesis of tetrasubstituted vinyl sulfides leading to a library of AIEgens

Tetraarylethylenes exhibit intriguing photophysical properties and sulfur atom frequently play a vital role in organic photoelectric materials and biologically active compounds. Tetrasubstituted vinyl sulfides, which include both sulfur atom and tetrasubstituted alkenes motifs, might be a suitable skeleton for the discovery of the new material molecules and drug with unique functions and properties. However, how to modular synthesis these kinds of compounds is still challenging. Herein, a chemo- and stereo-selective Rh(II)-catalyzed [1,4]-acyl rearrangements of α-diazo carbonyl compounds and thioesters has been developed, providing a modular strategy to a library of 63 tetrasubstituted vinyl sulfides. In this transformation, the yield is up to 95% and the turnover number is up to 3650. The mechanism of this reaction is investigated by combining experiments and density functional theory calculation. Moreover, the “aggregation-induced emission” effect of tetrasubstituted vinyl sulfides were also investigated, which might useful in functional material, biological imaging and chemicalnsing via structural modification.

Synthetic Study on Carthamin, Part 4. Improved Synthesis of a C-Glycosyl Quinochalcone by Installation of a Side Chain through Regioselective De-O-methylation and Acyl Rearrangement

AbstractWe report an improved synthesis of a C-Glycosyl quinochalcone that is a key intermediate in our total synthesis of carthamin, a natural red pigment of traditional heritage. The C-glycosyl quinochalcone is prepared by regioselective de-O-methylation of a C-glycosyl bromodienone, and installation of a p-coumaroyl side chain through an O→C acyl rearrangement.

N-Acyltriazinedione; a Novel Acylating Reagent Synthesized from a Triazinone-Type Condensing Reagent.

In this paper, we report the synthesis of N-acyltriazinedione via the unexpected O-N acyl rearrangement of acyloxytriazinone and its utility as an acylating reagent. N-Acyltriazinedione can be isolated by silica gel column chromatography and reacts with amines in the absence of any base to give the corresponding amides in good yields.

Sir Robert Robinson—Minor Prophet, a most senior referee, a story of darkness and light

The story of the Tetrahedron Letters affair in 1973–1974 is described and lessons for Editors, Referees, and Authors are drawn from the TL affair and related correspondence of Sir Robert Robinson (Sir RR) (Nobel Laureate), a Minor Prophet. The TL affair centered at two related papers authored by Israel Agranat, et al. on reversible Friedel-Crafts acylations and acyl rearrangements. The first paper (A) was published in J. C. S. Chem. Comm. (1973); it was followed by the second paper (B), which contained a reference to A “in the press.” It was originally accepted for publication in TL, following a favorable review. However, a month later, it was rejected in view of the reviewer’s subsequent allegation of lack of novelty due to A. The TL Editor Professor Alan Roy Katritzky relied also on the opinion of one of the journal’s most senior referees, Sir Robert Robinson, the founder of Tetrahedron and Tetrahedron Letters and the Chairman of their Honorary Advisory Boards, who in 1973 was blind. The TL affair led to correspondences of Sir RR with Professor Ernst David Bergmann and with the Author. Paper B was published (after modifications) in 1974 in Synthetic Communications.

Pyrrolo[1,2-a]quinoxalines from chalcones: An alternate route

The synthesis of 2,4-disubstituted pyrrolo[1,2-a]quinoxalines from chalcones is reported. The key steps used are polyphosphoric acid (PPA) assisted acyl rearrangement of the pyrrole ring and Fe catalyzed reduction-cyclization leading to 2,4-disubstituted pyrrolo[1,2-a]quinoxalines. Despite the utilization of comparatively unreactive aromatic ketones, modest to good yields were obtained.

An efficient synthesis tetrazole and oxadiazole analogues of novel 2′-deoxy-C-nucleosides and their antitumor activity

Various tetrazole and oxadiazole C-nucleoside analogues were synthesized starting from pure α- or β-glycosyl-cyanide. The synthesis of glycosyl-cyanide as key precursor was optimized on gram-scale to furnish crystalline starting material for the assembly of C-nucleosides. Oxadizole C-nucleosides were synthesized via two independent routes. First, the glycosyl-cyanide was converted into an amidoxime which upon ring closure offered an alternative pathway for the assembly of 1,2,4-oxadizoles in an efficient manner. Second, both anomers of glycosyl-cyanide were transformed into tetrazole nucleosides followed by acylative rearrangement to furnish 1,3,4-oxadiazoles in high yields. These protocols offer an easy access to otherwise difficult to synthesize C-nucleosides in good yield and protecting group compatibility. These C-nucleosides were evaluated for their antitumor activity. This work paves a path for facile assembly of library of new chemical entities useful for drug discovery.

Biochemical and Structural Characterization of an Unusual and Naturally Split Class 3 Intein.

Split inteins are indispensable tools for protein engineering because their ligation and cleavage reactions enable unique modifications of the polypeptide backbone. Three different classes of inteins have been identified according to the nature of the covalent intermediates resulting from the acyl rearrangements in the multistep protein‐splicing pathway. Class 3 inteins employ a characteristic internal cysteine for a branched thioester intermediate. A bioinformatic database search of non‐redundant protein sequences revealed the absence of split variants in 1701 class 3 inteins. We have discovered the first reported split class 3 intein in a metagenomics data set and report its biochemical, mechanistic and structural analysis. The AceL NrdHF intein exhibits low sequence conservation with other inteins and marked deviations in residues at conserved key positions, including a variation of the typical class‐3 WCT triplet motif. Nevertheless, functional analysis confirmed the class 3 mechanism of the intein and revealed excellent splicing yields within a few minutes over a wide range of conditions and with barely detectable cleavage side reactions. A high‐resolution crystal structure of the AceL NrdHF precursor and a mutagenesis study explained the importance and roles of several residues at the key positions. Tolerated substitutions in the flanking extein residues and a high affinity between the split intein fragments further underline the intein's future potential as a ligation tool.

A structural chemistry practitioner: a fox rather than a hedgehog. Reversibility of Friedel–Crafts acyl rearrangements

A retrospective review of reversibility revealed in Friedel–Crafts acyl rearrangements of polycyclic aromatic ketones derived from the polycyclic aromatic hydrocarbons naphthalene, phenanthrene, anthracene, fluorene, pyrene, and fluoranthene is presented. The reactions were carried out in polyphosphoric acid (PPA). A distinction is made between completely reversible reaction (equilibrium reaction) denoted by ⇌ and reaction, both directions denoted by ⇆. Reaction, both direction is considered reversible reaction, not completely reversible reaction. Gore’s 1955 proposition that Friedel–Craft acylation of reactive hydrocarbons is a reversible process has been verified. Complete reversibility has been revealed in ortho ⇌ para acyl rearrangements of fluorofluorenones (1FFL ⇌ 3FFL) and in dibenzofluorenones (DBahFL ⇌ DBbhFL). Both cases are intramolecular acyl rearrangements. The majority of reversible intramolecular and intermolecular Friedel–Crafts acyl rearrangements are formally “reaction, both directions,” e.g., dibenzoylpyrenes 1,6-Bz2PY ⇆ 1,8-Bz2PY. Acyl rearrangements and reversibility in Friedel–Crafts acylations are associated with thermodynamic control. However, sometimes kinetic control wins out over thermodynamic control. Polycyclic aromatic ketones in which the carbonyl group is coplanar with the aromatic nucleus may undergo Friedel–Crafts acyl rearrangements. The reversibility concept has been applied to the synthesis of new and known linearly annelated polycyclic aromatic ketones by intramolecular Friedel–Crafts rearrangements of their angularly annelated constitutional isomers. A linkage between reversible Friedel–Crafts acyl rearrangements in PPA and the Scholl reaction has been established in benzoylnaphthalenes and in dibenzoylpyrenes. As a structural chemistry practitioner, the scientific personality of the first author belongs to the foxes, rather than to the hedgehogs.

In quest of reversibility of Friedel-Crafts acyl rearrangements in the pyrene series

Friedel-Crafts acyl rearrangements in PPA of diacetylpyrenes (80–120 °C), dibenzoylpyrenes (80–200 °C), and bis(4-flurobenzoyl)pyrenes (80–120 °C) and Scholl reactions in AlCl3/NaCl of dibenzoylpyrenes (140–200 °C) have been studied. The substrates were 1-AcPY, 2-AcPY, 1,3-Ac2PY, 1,6-Ac2PY, 1,8-Ac2PY, 2,7-Ac2PY, 1-BzPY, 1,6-Bz2PY, 1,8-Bz2PY, 1-4FBzPY, 1,6-4FBz2PY, 1,8-4FBz2PY. The mixtures of pyrene, 1-AcPY, 2-AcPY, 1,3-Ac2PY, 1,6-Ac2PY, 1,8-Ac2PY, and 2,7-Ac2PY were separated by HPLC. The following reversible intermolecular isomerizations were established: 1,6-Ac2PY ⇌ 1,8-Ac2PY, 1,6-Bz2PY ⇌ 1,8-Bz2PY, and 1,6-4'FBz2PY ⇌ 1,8-4'FBz2PY, albeit not in high yields. The results substantiate Gore’s 1955 proposition that “The Friedel–Crafts acylation reaction of reactive aromatic hydrocarbons is a reversible process.” The isomerizations reported here differ from the few previously reported completely reversible intramolecular Friedel-Crafts acyl rearrangements. At ≥ 140 °C, in PPA and in AlCl3/NaCl, 1,6-Bz2PY and 1,8-Bz2PY underwent a highly regioselective double Scholl reaction to give pyranthrone (3) and deacylations to 1-BzPy (and pyrene), followed by mono-Scholl reactions to give 8H-dibenzo[def,qr]chrysen-8-one (1), and 11H-indeno[2,1-a]pyren-11-one (2). The formation of 3 and not the expected tribenzo[a,ghi,o]perylene-7,16-dione (4) from 1,8-Bz2PY indicates that 1,8-Bz2PY has first undergone isomerization to 1,6-Bz2PY. The present study confirms the linkage between Friedel-Crafts acyl rearrangements and the Scholl reaction.

The linkage between reversible Friedel–Crafts acyl rearrangements and the Scholl reaction

Friedel–Crafts acyl rearrangements in PPA (at 80–240 °C) and Scholl reactions in AlCl3/NaCl (at 140–220 °C) of benzoylnaphthalenes and fluorobenzoylnaphthalenes have been studied experimentally as a function of temperature and time and computationally. 1BzNA, 2BzNA, 1-4FBzNA, 2-4FBzNA, 1-3FBzNA, 2-3FBzNA, 1-2FBzNA, and 2-2FBzNA were synthesized by classical Friedel–Crafts acylations of naphthalene with benzoyl chloride, benzene with 2-naphthoyl chloride, fluorobenzene with 1- and 2-naphthoyl chlorides and of naphthalene with fluorobenzoyl chlorides, and served as substrates in the investigation. Their structures have been determined by X-ray crystallography and verified by their 1H-, 13C-, and 19F-NMR spectra. 1BzNA, 1-4FBzNA, 1-3FBzNA, and 2-2FBzNA crystallized as the E-diastereomers, whereas 2BzAN, 1-2FBzAN, 2-4FBzAN, and 2-3FBzAN crystallized as the Z-diastereomers. The deviations of the carbonyl group from the naphthyl plane were higher as compared with the deviations from the phenyl plane and were considerably higher in the α-naphthyl ketones than in the β-naphthyl ketones. Intermolecular interactions due to C–H···O and/or C–H···F contacts in the crystal structures of 1E-4FBzNA and 1E1′E-3FBzAN have been revealed. 1BzNA rearranged in PPA under argon to 2BzNA via deacylation to naphthalene (e.g., 140 °C, 10 h) and underwent a regioselective intramolecular cyclodehydrogenation at high temperatures to the Scholl reaction product 7H-benz[de]anthracen-7-one (BdeAN) (e.g., 200 °C, 6 h). At 80 °C, benzene was isolated. 2BzNA underwent in PPA deacylation to naphthalene (e.g., 160 °C, 6 h) and an intramolecular cyclodehydrogenation to BdeAN at high temperatures (e.g., 220 °C, 6 h), necessarily via the putative intermediate 1BzNA. Higher yields of the acyl rearrangement and the Scholl reaction products were obtained under oxygen. 1-4FBzNA and 2-4FBzNA reacted in PPA analogously to 1BzNA and 2BzNA, respectively, with the following exceptions: 2-4FBzNA underwent an acyl rearrangement in PPA to 1-4FBzNA at 260–300 °C, without any formation of the Scholl reaction product 10FBdeAN. 1-4FBzNA also did not yield 10FBdeAN. 1-2FBzNA and 2-2FBzNA behaved similarly. The formation of naphthalene and benzene in the deacylation steps indicated cleavages of both the 1- and 2-naphthyl–benzoyl bonds and the 1- and 2-naphthoyl–phenyl bonds to give naphthalene and benzoylium cation and benzene and 1- and 2-naphthoylium cation, respectively. At 80–100 °C, 1-2FBzNA, 1-3FBzNA, and 1-4FBzNA underwent deacylations to fluorobenzene in PPA, followed by reacylation, each giving a mixture of the three 1-fluorobenzoylnaphthalenes. 2FBzNA, 2-3FBzNA, and 2-4FBzNA behaved similarly, each giving a mixture of the three 2-fluorobenzoylnaphthalenes. The results taken together verified the reversibility of the 1-BzNA⇌2BzNA acyl rearrangements in PPA. The Scholl reaction (AlCl3/NaCl) of 1BzNA (e.g., at 140 °C) gave BdeAN and 2BzNA, whereas 2BzNA gave only BdeAN (at 200–220 °C). 1-4FBzNA and 2-4FBzNA gave (at 200–220 °C) only 2-4FBzNA and 1-4FBzNA, respectively. All the six FBzNA isomers failed to undergo Scholl reaction cyclodehydrogenations to give any FBdeAN isomer. A linkage between the Friedel–Crafts acyl rearrangements and the Scholl reaction has thus been established. A systematic DFT study at B3LYP/6-311(d,p)/PCM (formic acid)) substantiated the predicted mechanism and the reversibility of the acyl rearrangements of benzoylnaphthalenes, in which 1BzNA and 2BzNA are the kinetically controlled and the thermodynamically controlled products, respectively. The DFT-calculated Gibbs free-energy of the transition-state (1Z-1BzNH+ ➔➔ 2σ-2BzNA) in the Friedel–Crafts acyl rearrangement of 1Z-BzNA is considerably lower than the transition state of the cyclization step in the arenium-cation mechanism of the Scholl reaction, in line with experiment, which indicated higher temperatures for the Scholl reaction. DFT calculations of the dication pathway of the Scholl reaction of the E- and Z-diastereomers/conformers of 1BzNA confirmed the preference of the formation of BdeAN versus BaFL, consistently with experiment.

Application of Polyphosphoric Acid‐Mediated Acyl Migration for Regiospecific Synthesis of Diverse 2‐Acylpyrroles from Chalcones

A metal‐free approach for the synthesis of 2‐acylpyrroles is reported in this paper. Synthesis of the target molecule started from chalcones and was carried out in two steps. Initial step involved the conversion of chalcones to corresponding 4‐substituted‐3‐acylpyrroles by reaction with TosMIC. In the subsequent step, target molecules were obtained in modest to good yields by polyphosphoric acid‐mediated acyl rearrangement of 3‐acylpyrroles to their 2‐acyl congeners. The crucial final step was amenable to diverse substitutions on pyrrole ring. Preliminary experiment for the determination of mechanism indicated the involvement of acylium ion.

Highly diastereoselective C → N acyl rearrangement in polysubstituted pyrrolidine 2,2-dicarboxylates. Stereocontrolled synthesis of densely functionalized prolines

A fully diastereoselective C–N acyl transfer reaction operates in enantiopure densely substituted pyrrolidine 2,2-dicarboxylates.

A Computational Investigation of the Uncatalysed and Water-Catalysed Acyl Rearrangements in Ingenol Esters

Ingenol esters have been identified as potent anticancer and HIV latency reversing agents. Ingenol-3-angelate was recently approved as a topical treatment for precancerous actinic keratosis skin lesions. It was found, however, that ingenol esters can undergo a series of acyl rearrangements, which may affect their biological potency and the shelf-life of drug formulations. We use double-hybrid density functional theory to explore the mechanisms for the uncatalysed and water-catalysed acyl migrations in a model ingenol ester. The uncatalysed reaction may proceed either via a concerted mechanism or via a stepwise mechanism that involves a chiral orthoester intermediate. We find that the stepwise pathway is kinetically preferred by a significant amount of ΔΔH‡298 = 44.5 kJ mol−1. The uncatalysed 3-O-acyl to 5-O-acyl and 5-O-acyl to 20-O-acyl stepwise rearrangements involve cyclisation and ring-opening steps, both concomitant with a proton transfer. We find that the ring-opening step is the rate-determining step for both rearrangements, with reaction barrier heights of ΔH‡298 = 251.6 and 177.1 kJ mol−1 respectively. The proton transfers in the cyclisation and ring-opening steps may be catalysed by a water molecule. The water catalyst reduces the reaction barrier heights of these steps by over 90 kJ mol−1.

Zinc‐Catalyzed Esterification of N‐β‐Hydroxyethylamides: Removal of Directing Groups under Mild Conditions

Amide transformations involving C–N bond cleavage are recognized as difficult reactions owing to the inert nature of amides resulting from resonance. Accordingly, a strong inductive effect and geometrical distortion reasonably decrease the resonance stabilization to attenuate the C–N linkage. Although the conversion of such activated amides has been studied intensively, reaction systems for “unactivated” amides are underdeveloped. We herein report that a zinc(II) trifluoromethanesulfonate [Zn(OTf)2] catalyst achieves the esterification of a wide range of unactivated tertiary amides with the assistance of intramolecular acyl rearrangement. The reaction was applied to the one‐pot removal of various amide‐based directing groups under mild reaction conditions to afford the corresponding esters in high yields.

Friedel–Crafts acyl rearrangements in the fluoranthene series

Friedel–Crafts monoacylation and diacylation of fluoranthene (FT) gave 3-acetyl-, 8-acetyl-, 3-benzoyl-, 8-benzoyl-, 3-(4-fluorobenzoyl)-, 8-(4-fluorobenzoyl)-, 3,9-diacetyl-, 3,9-dibenzoyl-, and 3,9-bis(4-fluorobenzoyl)fluoranthene (3-AcFT, 8-AcFT, 3-BzFT, 8-BzFT, 3-(4-FBz)FT, 8-(4-FBz)FT, 3,9-Ac2FT, 3,9-Bz2FT, and 3,9-(4-FBz)2FT). The crystal and molecular structures of 8-AcFT, 3,9-Ac2FT, 7,10-Ac2FT, 3-BzFT, 8-BzFT, and 3-(4-FBz)FT were determined by X-ray crystallography. The structures of the fluoranthene derivatives, including 3,9-Ac2FT were verified by 1H-, 13C-, and 19F-NMR spectroscopy. The Friedel–Crafts acyl rearrangements in PPA of the above fluoranthene derivatives were studied at various temperatures and times. The kinetically controlled product 3-AcFT/3-BzFT rearranged to the thermodynamically-controlled product 8-AcFT/8-BzFT, not vice versa. 3,9-Ac2FT, 3,9-Bz2FT, and 3,9-(4-FBz)2FT underwent deacylation in PPA to give 8-AcFT, 8-BzFT, and 8-(4-FBz)FT, respectively. Deacetylation of 3,9-Ac2FT gave also 3-methyl-1H-benzo[cd]fluoranthene (3-MeBcdFT). The rich Friedel–Crafts acylation chemistry in PPA revealed in the fluoranthene series is characterized by regioselectivity. DFT calculations at B3LYP/6-31G(d) supported the regioselectivity including the formation of 3,9-Ac2FT, and the win of kinetic control over thermodynamic control.