Oxidative Ring Contraction Research Articles

Metal-free Oxidations with m-CPBA: An Octennial Update

Abstract: meta-Chloroperbenzoic acid (mCPBA) is a readily available peroxide that is a powerful oxidizing agent utilized in a range of oxidative reactions. Metal-free oxidations mediated by mCPBA involving selective oxidation of aliphatic amines to oximes, selective oxidation of organosulphides/ aldehydes, synthesis of heterocyclic N-oxides, domino C[sp2] hydroxylation/ annulation of enaminones (heterocyclic ring formation), acid to phenol conversion, oxidation of exocyclic C=C bond, oxidative ring contraction, etc. have been comprehensively and critically examined in this mini-review from 2015 to date.

2-Benzoyl-4-phenyl-1,2,5-thiadiazol-3(2H)-one 1,1-Dioxide

3,5-Diphenyl-4H-1,2,6-thiadiazin-4-one treated with meta-chloroperoxybenzoic acid undergoes an oxidative ring contraction to give 2-benzoyl-4-phenyl-1,2,5-thiadiazol-3(2H)-one 1,1-dioxide in a 29% yield, the structure of which is supported by single-crystal X-ray diffraction analysis and the available spectroscopic data.

A novel approach to the tetracyclic frameworks of anislactone-type sesquiterpenoids

A novel approach for synthesizing the A-B-C-D ring system of anislactone-type sesquiterpenoids was enabled by a H2O2-mediated oxidative ring contraction reaction.

Synthesis of Spiro-oxindoles (Spiroindolones) via Oxidative Ring Contraction Approach

Abstract: Ring contraction reaction is among the several vital strategies in organic synthesis that can provide very diversified and useful molecular architecture. Among these strategies, the oxidative ring contraction is of special interest as it can give a more straightforward way of designing and synthesizing several complex natural products, specifically the oxindole alkaloids and some newer oxindole analogs. Even this methodology can be expanded to prepare dispiro-bisoxindoles-type compounds besides the dipolar cycloaddition methodology. In this review, we have tried to collect the reports on oxidative ring contraction reactions using several oxidants, like tert-Butyl hypochlorite, oxaziridine, dimethyldioxirane, N-bromosuccinimide, etc., in different reaction conditions for the synthesis of spiro-oxindole natural products as well as newer synthetic analogs.

Asymmetric Synthesis of trans-3-Alkoxyamino-4-Oxygenated-2-Piperidones Mediated by Transition-Metal-Free Dual C-H Oxidation and Its CAL-B-Assisted Enzymatic Resolution

A general chemo-enzymatic approach to synthesize both enantioenriched trans-3-alkoxyamino-4-oxy-2-piperidones, which are important scaffold for various naturally occurring alkaloids, is reported. To this end, a selective transition-metal-free dual C−H oxidation of piperidines mediated by the TEMPO oxoammonium cation (TEMPO+) was used, followed by enzymatic resolution of the corresponding alkoxyamino-2-piperidones with Candida antarctica lipase (CAL-B), to yield the title compounds in high enantiomeric excess (ee). The absolute configuration of both enantioenriched compounds was determined using chemical correlation and circular dichroism (CD) spectroscopy. The former method highlights the oxidative ring contraction of the trans-alkoxyamine-2-piperidone ring into its corresponding 2-pyrrolidinone.

Changing Fates of the Substrate Radicals Generated in the Active Sites of the B12-Dependent Radical SAM Enzymes OxsB and AlsB.

OxsB is a B12-dependent radical SAM enzyme that catalyzes the oxidative ring contraction of 2'-deoxyadenosine 5'-phosphate to the dehydrogenated, oxetane containing precursor of oxetanocin A phosphate. AlsB is a homologue of OxsB that participates in a similar reaction during the biosynthesis of albucidin. Herein, OxsB and AlsB are shown to also catalyze radical mediated, stereoselective C2'-methylation of 2'-deoxyadenosine monophosphate. This reaction proceeds with inversion of configuration such that the resulting product also possesses a C2' hydrogen atom available for abstraction. However, in contrast to methylation, subsequent rounds of catalysis result in C-C dehydrogenation of the newly added methyl group to yield a 2'-methylidene followed by radical addition of a 5'-deoxyadenosyl moiety to produce a heterodimer. These observations expand the scope of reactions catalyzed by B12-dependent radical SAM enzymes and emphasize the susceptibility of radical intermediates to bifurcation along different reaction pathways even within the highly organized active site of an enzyme.

Concise synthesis of piperarborenine B

A concise synthesis of piperarborenine B is reported. Organocatalytic electrophilic amination of pyrrolidines, stereospecific oxidative ring contraction and an original diastereoselective Krapcho dealkoxycarbonylation/transmethylation contribute to a novel synthetic strategy to the preparation of a non-symmetrical cyclobutane core. Being transition-metal-free, directing-group-free and protecting-group-free, a five-step synthesis of piperarborenine B was accomplished.

Structural Investigation of AlsA, a Radical S‐adenosylmethionine Enzyme Involved in the Biosynthesis of the Oxetane‐containing Herbicide Albucidin

Herbicides are a class of molecules commonly employed to maintain high crop yields by targeting weeds, a particularly damaging class of pests in agriculture. Albucidin is a novel herbicide found in Streptomyces albus subsp. Chlorinus NRRL B‐24108 that shows a suspected new mode of action. Albucidin is a nucleoside analogue containing an oxetane moiety similar to the antiviral compound oxetanocin‐A (OXT‐A). OXT‐A is the only other known naturally occurring oxetane‐containing nucleoside analogue and has a biosynthetic pathway with two key enzymes: OxsA and OxsB. OsxB is a B12‐dependent radical S‐adenosylmethionine (RS) enzyme and catalyzes formation of the oxetane ring via an oxidative ring contraction. A similar reaction has been proposed to be catalyzed by the B12‐dependent RS enzyme AlsB in the biosynthetic pathway of albucidin; however, the two biosynthetic pathways appear to diverge at this point as well. While OXT‐A is formed upon subsequent reduction and OxsA catalyzed dephosphorylation of the OxsB reaction product, the chemistry leading to albucidin is much less clear. In particular, one carbon must be eliminated, and AlsA, which is a biotin synthase‐like RS enzyme also encoded in the albucidin biosynthetic cluster, has been proposed to participate in this reaction. AlsA is most closely related to BioB‐like enzymes and demonstrates high sequence similarity with the canonical TIM barrel domain; however, AlsA also contains an N‐terminal domain of about 100 amino acids that shares minimal sequence homology to other RS enzymes with known structures. Herein, recent developments in the structural analysis of AlsA using X‐ray crystallography are reported.

Studies of GenK and OxsB, two B12-dependent radical SAM enzymes involved in natural product biosynthesis.

The B12-dependent radical SAM enzymes are an emerging subgroup of biological catalysts that bind a cobalamin cofactor in addition to the canonical [Fe4S4] cluster characteristic of radical SAM enzymes. Most of the B12-dependent radical SAM enzymes that have been characterized mediated methyltransfer reactions; however, a small number are known to catalyze more diverse reactions such as ring contractions. Thus, Genk is a methyltransferase from the gentamicin C biosynthetic pathway, whereas OxsB catalyzes the oxidative ring contraction of 2'-deoxyadenosine 5'-phosphates to generate an oxetane aldehyde during the biosynthesis of oxetanocin A. The preparation and in vitro characterization of such enzymes is complicated by the presence of two redox sensitive cofactors in addition to challenges in obtaining soluble protein for study. This chapter describes expression, purification and assay methodologies for GenK and OxsB highlighting the use of denaturation/refolding protocols for solubilizing inclusion bodies as well as the use of cluster assembly and cobalamin uptake machinery during in vivo expression.

A concise synthesis of herbertenolide.

A concise synthesis of (±)-herbertenolide has been accomplished herein. The strategy relies on a H2O2-mediated oxidative ring contraction of all-substituted cyclic α-formyl ketones for the stereospecific construction of contiguous quaternary carbon centers (CQCCs). Furthermore, a Sc(OTf)3/chiral N,N'-dioxide catalyzed asymmetric Michael addition of benzofuranone to MVK has been optimized for forging a chiral aromatic quaternary carbon center, which enables the formal synthesis of (+)-ent-herbertenolide.

Early Oxidative Transformations During the Biosynthesis of Terrein and Related Natural Products.

The mycotoxin terrein is derived from the C10‐precursor 6‐hydroxymellein (6‐HM) via an oxidative ring contraction. Although the corresponding biosynthetic gene cluster (BGC) has been identified, details of the enzymatic oxidative transformations are lacking. Combining heterologous expression and in vitro studies we show that the flavin‐dependent monooxygenase (FMO) TerC catalyzes the initial oxidative decarboxylation of 6‐HM. The reactive intermediate is further hydroxylated by the second FMO TerD to yield a highly oxygenated aromatic species, but further reconstitution of the pathway was hampered. A related BGC was identified in the marine‐derived Roussoella sp. DLM33 and confirmed by heterologous expression. These studies demonstrate that the biosynthetic pathways of terrein and related (polychlorinated) congeners diverge after oxidative decarboxylation of the lactone precursor that is catalyzed by a conserved FMO and further indicate that early dehydration of the side chain is an essential step.

Synthesis of Dihydropyrrole Derivatives by Oxidative Functionalization of 2-Amino-4H-Chromenes Using Hypervalent Iodine Reagents

AbstractAn efficient simple, metal-free, one-pot protocol for the synthesis of dihydropyrrole derivatives has been achieved via sequential addition of iodobenzenediacetate and secondary amine to 2-amino-4H- pyran derivatives. The one-pot protocol proceeds through tandem oxidative functionalization, rearrangement, and ring contraction to provide an entirely new strategy for the construction of the dihydropyrrole skeleton.

Biosynthesis of Oxetanocin-A Includes a B12-Dependent Radical SAM Enzyme That Can Catalyze both Oxidative Ring Contraction and the Demethylation of SAM.

Oxetanocin-A is an antitumor, antiviral, and antibacterial nucleoside. It is biosynthesized via the oxidative ring contraction of a purine nucleoside co-opted from primary metabolism. This reaction is catalyzed by a B12-dependent radical S-adenosyl-l-methionine (SAM) enzyme, OxsB, and a phosphohydrolase, OxsA. Previous experiments showed that the product of the OxsB/OxsA-catalyzed reaction is an oxetane aldehyde produced alongside an uncharacterized byproduct. Experiments reported herein reveal that OxsB/OxsA complex formation is crucial for the ring contraction reaction and that reduction of the aldehyde intermediate is catalyzed by a nonspecific dehydrogenase from the general cellular pool. In addition, the byproduct is identified as a 1,3-thiazinane adduct between the aldehyde and l-homocysteine. While homocysteine was never included in the OxsB/OxsA assays, the data suggest that it can be generated from SAM via S-adenosyl-l-homocysteine (SAH). Further study revealed that conversion of SAM to SAH is facilitated by OxsB; however, the subsequent conversion of SAH to homocysteine is due to protein contaminants that co-purify with OxsA. Nevertheless, the observed demethylation of SAM to SAH suggests possible methyltransferase activity of OxsB, and substrate methylation was indeed detected in the OxsB-catalyzed reaction. This work is significant because it not only completes the description of the oxetanocin-A biosynthetic pathway but also suggests that OxsB may be capable of methyltransferase activity.

Synthetic Biology Driven Biosynthesis of Unnatural Tropolone Sesquiterpenoids.

Tropolone sesquiterpenoids (TS) are an intriguing family of biologically active fungal meroterpenoids that arise through a unique intermolecular hetero Diels–Alder (hDA) reaction between humulene and tropolones. Here, we report on the combinatorial biosynthesis of a series of unprecedented analogs of the TS pycnidione 1 and xenovulene A 2. In a systematic synthetic biology driven approach, we recombined genes from three TS biosynthetic gene clusters (pycnidione 1, xenovulene A 2 and eupenifeldin 3) in the fungal host Aspergillus oryzae NSAR1. Rational design of the reconstituted pathways granted control over the number of hDA reactions taking place, the chemical nature of the fused polyketide moiety (tropolono‐ vs. monobenzo‐pyranyl) and the degree of hydroxylation. Formation of unexpected monobenzopyranyl sesquiterpenoids was investigated using isotope‐feeding studies to reveal a new and highly unusual oxidative ring contraction rearrangement.

N-Chlorination-induced, oxidative ring contraction of 1,4-dimethoxyphthalazines

A rarely explored oxidative ring contraction of electron-rich 1,2-diazine is described. Upon treatment with an electrophilic chlorinating reagent (TCICA), 1,4-dimethoxyphthalazines undergo an N-chlorination-induced ring contraction that is accompanied by the loss of one nitrogen atom. The scope of this unusual reactivity was examined with a range of 1,4-dimethoxyphthalazine derivatives. In addition, a mechanism proceeding via a bicyclic species was proposed on the basis of an isolated reaction intermediate and DFT calculations.

Synthesis of spiro[indolizidine-1,3′-oxindole] from l-glutamic acid

Spiro[indolizidine-1,3′-oxindole] compounds have been synthesized in enantiomerically pure form from l-glutamic acid. The key oxidative ring contraction of chiral indolo[2,3-a]quinolizidinone was achieved by treatment with N-bromosuccinimide in tetrahydrofuran/water in the presence of catalytic trifluoroacetic acid. The stereochemistry of the reaction was controlled by the dibenzylamino group which could be subsequently removed using Cope elimination.

Synthesis of internally alkylated azuliporphyrins

Examples of internally alkylated azuliporphyrins were prepared by MacDonald-type “3 + 1” condensations. 2-Methyl- and 2-ethylazulene reacted with an acetoxymethylpyrrole in the presence of an acid catalyst to give azulitripyrranes. Following cleavage of the terminal protective groups, condensation with a diformylpyrrole in the presence of hydrochloric acid and oxidation with ferric chloride afforded 21-alkylazuliporphyrins. An azulene dialdehyde similarly reacted with an [Formula: see text]-methyltripyrrane to generate a 23-methylazuliporphyrin. The products could only be isolated in protonated form and the free-base internally alkylated azuliporphyrins proved to be unstable. Nevertheless, the dications are highly diatropic and the internal alkyl group resonances were shifted upfield to beyond -3 ppm. Reaction of a 23-methylazuliporphyrin with palladium(II) acetate primarily afforded a palladium(II) complex with loss of the internal methyl substituent. However, two palladium(II) benzocarbaporphyrins were also identified that were formed by sequential oxidative ring contraction and methyl group migration. Internally alkylated azuliporphyrins provide new insights into the reactivity of the system and the results show that the introduction of alkyl substituents within porphyrinoid cavities greatly modifies the properties of these structures.

Iodine Promoted One‐Pot Synthesis of 2‐Aryl Benzoxazoles from Amidoximes via Oxidative Cyclization and Ring Contraction

A molecular I2‐promoted one‐pot synthesis of 2‐aryl benzoxazoles has been developed by using amidoximes rather than the limited 2‐aminophenols or 2‐haloamides as substrates. The amidoxime substrates provided unique and efficient strategies for converting readily available aniline and benzaldehyde precursors into valuable chemicals. This transformation proceeded smoothly under transition‐metal‐free conditions through a sequential oxidative cyclization and ring contraction, and provided a potential route for introducing certain groups at any site of the scaffold.

Mechanism and Selectivity of the Oxidative Ring Contraction of Cyclic α-Formyl Ketones.

The oxidative contraction of α-formal ketone to form continuous all carbon chiral centers promoted by H2 O2 is widely used in natural product total synthesis. Typically, using this transformation, chiral cyclic ketones are obtained as the major products and ring-opening products as the minor products. Herein, DFT calculations have been used to investigate the detailed reaction mechanism and chemoselectivity. In addition, with the widely accepted mechanism of H2 O2 -promoted transformation, our systematic investigation with various explicit-solvent-model calculations for the first time shows that H2 O and H2 O2 are comparable at catalyzing the rate-determining step of this reaction, which emphasis the importance of solvent effect in such transformations. It is found that both the less ring-constrain and a later transition state in an exothermic reaction account for the origin why the reaction favors ring-contraction pathway rather than ring-opening one. By a comprehensive analysis for the substituted groups, it has been disclosed that the steric effects of the substituted groups on R2 and R3 contribute to the selectivity with larger steric hindrance favoring the chiral cyclic products. Moreover, the electronic effects on R1 but not R3 affect the selectivity with electron-donating groups leading to the cyclic products. Based on our calculations, some predictions for higher selectivity have been made.

Concise syntheses of (+)-austrodoral and (+)-austrodoric acid Based on H2O2 mediated oxidative ring contraction

Asymmetric synthesis of the marine nor-sesquiterpenoid (+)-austrodoric acid and (+)-austrodoral in seven and nine steps respectively from Wieland-Miescher ketone was described herein. The synthesis featured an oxidative ring contraction of α-formyl cyclic ketone mediated by H2O2 to forge the hydrindane scaffold together with the contiguous quaternary carbon centers simultaneously.