Two-carbon Homologation Research Articles

Transition Metal-Free Domino Hydroamination/Isomerization/Transamidation Sequence: An Entry to Trifluorinated γ-Lactams.

A method for the construction of trifluorinated-5-methylenepyrrolidinone is reported. This strategy combines an acid-catalyzed two-carbon homologation process between ynamides and aldehydes, providing CF3-substituted dienes followed by a metal-free domino hydroamination/isomerization/transamidation sequence, delivering trifluorinated-5-methylenepyrrolidinone stereoselectively.

An Overview of One and Two Carbon Homologation and Homologation- Functional Group Interconversion Reactions in Organic Synthesis

Abstracts: The extension of carbon chains, known as homologation, is one of the most fundamental operations of organic synthesis. One and two-carbon homologation reactions are of immense importance because they can be used for synthesizing members of a homologous series by iterative operations. Homologation reactions produce higher analogues of the same functional group, whereas homologation- functional group interconversion (FGI) generates higher analogues with a change in functionality. This general synthesis strategy may be counted for a number of reasons, such as higher accessibility to the successive homologs, a chance for the introduction of additional functionality, or solely to create a regular series of homologs. The advantages of homologation reactions could be measured by the efficiency, technical simplicity, and regio- and/or stereo-selectivity of the overall operations in a synthetic plan. Homologation reactions constitute powerful and versatile tools for preparative chemistry which uses different concepts underpinning the use of homologating reagents in addition to their applications in organic synthesis. A compilation and comparison of diverse methods available for homologation cum functional group interconversion will empower synthetic chemists to undertake studies that require a series of analogues. In this review, we have categorized and summarized such methods and synthetic applications of one and two-carbon homologation-functionalization of various functional groups in organic synthesis.

An Alternative Formal Synthesis of (S)-(+)-Vigabatrin

AbstractAn improved synthesis of chirally pure advanced pyrrolidone intermediate of the (S)-(+)-vigabatrin, an antiseizure active pharmaceutical ingredient (API) is reported. The synthesis is developed using commercially available, cheaper amino acid (R)-methionine. Meldrum’s acid served as a two-carbon homologation unit to access the pyrrolidone intermediate in a short synthetic sequence. The sequence to pyrrolidone intermediate is scalable and eludes the use of organometallic pyrophoric reagents on a large scale.

Stereoselective two-carbon ring expansion of allylic amines via electronic control of palladium-promoted equilibria.

General methodologies enabling the two-carbon homologation of pyrrolidine and piperidine systems have yet to be developed. Herein we report that palladium-catalysed allylic amine rearrangements enable efficient two-carbon ring expansion of 2-alkenyl pyrrolidine and piperidines to their azepane and azocane counterparts. Conditions are mild, tolerant of a range of functional groups and the process can occur with high enantioretention. The products formed undergo a range of orthogonal transformations, making them ideal scaffolds for the creation of compound libraries.

Two-Carbon Ring Expansion of Cyclobutanols to Cyclohexenones Enabled by Indole Radical Cation Intermediate: Development and Application to a Total Synthesis of Uleine

A single-electron transfer (SET) oxidation of indole or benzo[b]thiophene to a radical cation reverses the intrinsic polarity of these π-excessive bicyclic heteroarenes. Here we report an oxidative two-carbon homologation of cyclobutanols to cyclohexenones under a visible-light photoredox catalysis. 1-(Indol-2-yl)cyclobutan-1-ols are converted to 2,3,4,9-tetrahydro-1H-carbazol-1-ones, important structural motifs found in alkaloids and pharmaceuticals, with a broad substrate scope. A mechanistic study suggests that the reaction is initiated by an SET from an indole to an excited acridinium salt to generate the radical cation, which is followed by two consecutive 1,2-alkyl migrations and a rearomatization. Benzo[b]thiophene-substituted cyclobutanols are similarly converted to 2,3-dihydrodibenzo[b,d]thiophen-4(1H)-ones. A total synthesis of (±)-uleine featuring this ring-expansion process is documented.

One and Two-Carbon Homologation of Primary and Secondary Alcohols to Corresponding Carboxylic Esters Using β-Carbonyl BT Sulfones as a Common Intermediate.

Herein we report the efficient one- and two-carbon homologation of 1° and 2° alcohols to their corresponding homologated esters via the Mitsunobu reaction using β-carbonyl benzothiazole (BT) sulfone intermediates. The one-carbon homologation approach uses standard Mitsunobu C-S bond formation, oxidation and subsequent alkylation, while the two-carbon homologation uses a less common C-C bond forming Mitsunobu reaction. In this latter case, the use of β-BT sulfone bearing esters lowers the p Ka sufficiently enough for the substrate to be used as a carbon-based nucleophile and deliver the homologated β-BT sulfone ester, and this superfluous sulfone group can then be cleaved. In this paper we describe several methods for the effective desulfonylation of BT sulfones and have developed methodology for one-pot alkylation-desulfonylation sequences. As such, overall, a one-carbon homologation sequence can be achieved in a two-pot (four step) procedure and the two-carbon homologation in a two-pot (three step) procedure (three-pot; four step when C-acid synthesis is included). This methodology has been applied to a wide variety of functionality (esters, silyl ethers, benzyls, heteroaryls, ketones, olefins and alkynes) and are all tolerated well providing good to very good overall yields. The power of our method was demonstrated in site-selective ingenol C20 allylic alcohol two-carbon homologation.

Indium- and Zinc-Mediated Acyloxyallylation of Protected and Unprotected Aldotetroses-Revealing a Pronounced Diastereodivergence and a Fundamental Difference in the Performance of the Mediating Metal.

The acyloxyallylation of unprotected aldoses was first demonstrated more than a decade ago as a potentially elegant two-carbon homologation of reducing sugars (upon ozonolysis); however, its application in real case syntheses remained scarce. Following up on such a successful showcase and to answer several pending questions about this attractive transformation, we engaged in an in depth methodological reinvestigation. The epimeric tetroses l-erythrose and d-threose in unprotected and protected form were successfully applied to the indium and also zinc-mediated acyloxyallylation, with the latter being a first for an unprotected sugar. The investigation largely benefited from the choice of these more exotic starting materials as it allowed unambiguous identification/quantification of the hexose-products which are available as authentic reference materials. The observed diastereoselectivities indicate a strong substrate control (stereochemistry at O2), and the influence of the reagent’s structure on the selectivity was investigated in great detail. A strong facial diastereodivergence between related protected and unprotected structures was demonstrated and an unexpected, pronounced principle difference in performance between indium and zinc was revealed.

NMR-Assisted Structure Elucidation of an Anticancer Steroid-β-Enaminone Derivative

The fortuitous modification of a quinoline-proline-piperazine side chain linked to a steroid in the presence of lithium (trimethylsilyl) acetylide has generated an unknown product that is more active than its precursor. After having characterized two β-enaminones (two-carbon homologation compounds) that were generated from a simplified model side chain, we have identified the unknown product as being the β-enaminone steroid derivative 1. NMR analysis, especially two-dimensional (2D) experiments (correlation spectroscopy (COSY), NOE spectroscopy (NOESY), heteronuclear single-quantum correlation (HSQC) and heteronuclear multiple-bond correlation (HMBC)) provided crucial information that was found essential in the characterization of enaminone 1. We also proposed a mechanism to rationalize the formation of this biologically active compound.

ChemInform Abstract: An Efficient Synthesis of 1,4‐Dideoxy‐1,4‐imino‐D‐ and L‐arabinitol and 1,4‐Dideoxy‐1,4‐imino‐D‐ and L‐xylitol from Chiral Aziridines.

Abstract A highly efficient method for the synthesis of 1,4-dideoxy-1,4-imino- d - and l -arabinitol ( d -AB1, 1 and l -AB1, 3 ) and 1,4-dideoxy-1,4-imino- d - and l -xylitol ( d -DIX, 2 and l -DIX, 4 ) starting from commercially available chiral aziridines was developed. The general strategy employs a sequence involving two-carbon homologation, dihydroxylation, and regioselective aziridine ring opening/intramolecular five-membered iminosugar ring formation. The facile use of recrystallization to generate pure diastereomers makes the routes more amenable to large-scale synthesis.

Modular Synthesis of Lamellarins via Regioselective Assembly of 3,4,5-Differentially Arylated Pyrrole-2-carboxylates

A modular synthesis of lamellarins via 3,4,5-differentially arylated pyrrole-2-carboxylate intermediates has been developed. The key reactions employed are Br-Li exchange-methoxycarbonylation of 2,5-dibromo-1-(tert-butoxycarbonyl)-1H-pyrrole (1) followed by palladium-catalyzed iterative Suzuki-Miyaura coupling of the pyrrole core. The 3,4,5-triarylpyrrole 4 thus synthesized was readily converted to 5,6-saturated lamellarin L (2) and 5,6-unsaturated lamellarin N (3) via lactonization followed by annulation of the pyrrole nitrogen and lateral aromatic ring at C5 using 2-bromoethyl phenyl sulfide or bromoacetaldehyde dimethyl acetal as two-carbon homologation agents. In principle, this strategy allows the production of diverse lamellarins in short steps with high yields using readily accessible arylboronic acids as aromatic modules.

ChemInform Abstract: Nitroethylation of Vinyl Triflates and Bromides.

A two-carbon homologation of vinyl triflates and bromides for the synthesis of homoallylic nitro products is described. This palladium-catalyzed double coupling of nitromethane exploits the anion stabilizing and leaving group properties of nitromethane, generating the homo allyl nitro products via a tandem cross-coupling/π-allylation sequence. The resultant process provides a mild and convenient entry to nitroethylated products, which are versatile precursors to β,γ-unsaturated carbonyls, homoallylic amines, and nitrile oxides.

An efficient synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol and 1,4-dideoxy-1,4-imino-d- and l-xylitol from chiral aziridines

A highly efficient method for the synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol (d-AB1, 1 and l-AB1, 3) and 1,4-dideoxy-1,4-imino-d- and l-xylitol (d-DIX, 2 and l-DIX, 4) starting from commercially available chiral aziridines was developed. The general strategy employs a sequence involving two-carbon homologation, dihydroxylation, and regioselective aziridine ring opening/intramolecular five-membered iminosugar ring formation. The facile use of recrystallization to generate pure diastereomers makes the routes more amenable to large-scale synthesis.

Nitroethylation of Vinyl Triflates and Bromides

A two-carbon homologation of vinyl triflates and bromides for the synthesis of homoallylic nitro products is described. This palladium-catalyzed double coupling of nitromethane exploits the anion stabilizing and leaving group properties of nitromethane, generating the homo allyl nitro products via a tandem cross-coupling/π-allylation sequence. The resultant process provides a mild and convenient entry to nitroethylated products, which are versatile precursors to β,γ-unsaturated carbonyls, homoallylic amines, and nitrile oxides.

Development of a robust reagent for the two-carbon homologation of aldehydes to (E)-α,β-unsaturated aldehydes in water

Synthesis of a new pinacolacetal-phosphonium salt and its reaction with aldehydes to give homologated acetals and two-carbon homologated unsaturated aldehydes is presented. The chemistry takes place in water under mild conditions and the sequence can be performed in one-flask operation.

A Continuous Homologation of Esters: An Efficient Telescoped Reduction–Olefination Sequence

A continuous protocol for the two-carbon homologation of esters to α,β-unsaturated esters is described. This multireactor homologation telescopes an ester reduction, phosphonate deprotonation, and Horner-Wadsworth-Emmons olefination, thus converting a three-operation procedure into a single, uninterrupted system that eliminates the need for isolation or purification of the aldehyde intermediates. The homologated products are obtained in high yield and selectivity.

Enals via a Simple Two-Carbon Homologation of Aldehydes and Ketones

Enals via a Simple Two-Carbon Homologation of Aldehydes and Ketones

Heteroannelated (+)-muricatacin mimics: synthesis, antiproliferative properties and structure–activity relationships

Six new (+)-muricatacin mimics bearing a furano-furanone core have been synthesized and their in vitro antiproliferative activity was evaluated against a panel of human tumour cell lines. A straightforward total synthesis of (+)-muricatacin ( 1) from d-xylose is disclosed providing a sample of 1 that served as a positive control in antitumour assays. All new compounds showed diverse antiproliferative effects against human malignant cell lines, but were devoid of any significant cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). Additionally, the most of (+)-muricatacin analogues show selective cytotoxicities towards certain cancer cell lines, whereas only two of six analogues are broadly toxic against all cell lines under evaluation. A SAR study reveals the structural features that may be beneficial for the antiproliferative activity of these lactones. These include the absolute stereochemistry, introduction of a THF ring, interchange of the O 8 ether functionality and the C 8 methylene group in the side chain of muricatacin oxa analogues, as well as the one- or two-carbon homologation of the side chain in both 3 and 6.

Two-Carbon Homologation of Aldehydes and Ketones to α,β-Unsaturated Aldehydes

Phosphonate reagents were developed for the two-carbon homologation of aldehydes or ketones to unbranched- or methyl-branched α,β-unsaturated aldehydes. The phosphonate reagents, diethyl methylformyl-2-phosphonate dimethylhydrazone and diethyl ethylformyl-2-phosphonate dimethylhydrazone, contained a protected aldehyde group instead of the usual ester group. A homologation cycle entailed condensation of the reagent with the starting aldehyde, followed by removal of the dimethylhydrazone protective group with a biphasic mixture of 1 M HCl and petroleum ether. This robust two-step process worked with a variety of aldehydes and ketones. Overall isolated yields of unsaturated aldehyde products ranged from 71% to 86% after the condensation and deprotection steps.

New Preparation of Diethyl Methylformyl-2-phosphonate Dimethylhydrazone: A Reagent for Aldehyde Homologation

The phosphonate reagent diethyl methylformyl-2-phosphonate dimethylhydrazone contains a protected aldehyde group instead of the usual ester group. It can be used for the two-carbon homologation of aldehydes to α, β-unsaturated aldehydes. The reagent can be prepared in good overall yield (82%) and purity by deprotection of commercially available diethyl-2,2-(diethoxy)ethylphosphonate with p-toluenesulfonic acid in 1.5% aqueous acetone to give diethyl formylmethyl-2-phosphonate, followed by a simple preparation of the dimethylhydrazone derivative with N,N-dimethylhydrazine.

ChemInform Abstract: A Pummerer-Type Novel Ring Fission of 2-Methylsulfinyl-5,6-dihydro-4H- 1,3,4-thiadiazine Derivatives: A Homologation of Aldehydes and Ketones.

Aldehydes and ketones were converted into 2-methylsulfinyl-5,6-dihydro-4H-1,3,4-thiadiazines via the formation and base-induced ring-closure of N-alkylidene-N′-bis(alkylthio)methylenehydrazines followed by mCPBA oxidation. The subsequent Pummerer-type ring fission of the rings was performed by treating with trifluoroacetic anhydride or trifluoromethanesulfonic anhydride at −78 °C to give α,β-unsaturated esters and ketones in modest yields. Thus, this reaction sequence was regarded as being a new method for the two-carbon homologation of aldehydes and ketones.