Total synthesis of linear lipodepsipeptide kavaratamide A and its C25-epimer.

We report the stereoselective total synthesis of kavaratamide A, a linear lipodepsipeptide from the cyanobacterium (collected in Kavaratti, India), and its unnatural C25-epimer. The convergent approach employs Keck asymmetric allylation to construct the chiral β-hydroxy carboxylic acid fragment [(3)-HDA; 3-hydroxydecanoic acid], while the peptide unit was assembled from L-Val, -Me-L-Ala, ()-Hiva, and ()-Pr--Me-pyr using well-orchestrated coupling methods to prevent racemization. Modifications to the Keck allylation conditions enabled the synthesis of the C25-epimer with good yield.

Studies on the Stereoselective Synthesis of Sacubitril via a Chiral Amine Transfer Approach.

We present a comprehensive account of our efforts directed towards the synthesis of sacubitril, a neprilysin inhibitor used in combination with valsartan and marketed as Entresto™. Our initial approach to the formal synthesis of sacubitril employed a chiral pool strategy, utilizing (S)-pyroglutamic acid as a key building block and Cu(I)-mediated Csp-Csp cross-coupling as a key transformation. Further investigations led to the development of chiral amine transfer (CAT) reagents-based stereoselective synthesis.

AgOTf-catalyzed cascade annulation of 5-hexyn-1-ols and aldehydes: enabling the diastereoselective synthesis of [6,6,6]-trioxa-fused ketals and hexahydro-2-chromenes.

We report the unprecedented diastereoselective synthesis of novel [6,6,6]-trioxa-fused ketals AgOTf-catalyzed cascade annulation of 5-hexyn-1-ols (with primary or secondary hydroxyl groups) and aldehydes through a [2+2+1+1] pathway. In contrast, 5-hexyn-1-ols with tertiary hydroxyl groups yield hexahydro-2-chromenes a [3+1+1+1] pathway.

Ready Access to [5,6,5]-Trioxa-spiro and Fused Ketals via Ag-Catalyzed Cascade Annulation of 4-Pentyn-1-ols and Aldehydes.

In this study, we unveil the versatility of 4-pentyn-1-ols as carbonyl surrogates for the unprecedented synthesis of diverse oxygen heterocycles, including [5,6,5]-bis-spiroketals (trioxadispiroketals) and [5,6,5]-furano-spiroketals related to bioactive natural products. These reactions commence with the π-activation-induced intramolecular hydroalkoxylation of 4-pentyn-1-ols, yielding cyclic enol ethers, which undergo subsequent three-component annulation with aldehydes in a [2+2+1+1] fashion, resulting in the formation of [5,6,5]-bis-spiroketals. Notably, the distinctive steric features of alkynyl alcohols, particularly those with a secondary or tertiary alcohol functionality, dictate divergent reaction pathways, leading to the formation of [5,6,5]-furano-spiroketals.

Structure of epoxide hydrolase 2 from Mangifera indica throws light on the substrate specificity determinants of plant epoxide hydrolases.

Epoxide hydrolases (EHs) are a group of ubiquitous enzymes that catalyze hydrolysis of chemically reactive epoxides to yield corresponding dihydrodiols. Despite extensive studies on EHs from different clades, generic rules governing their substrate specificity determinants have remained elusive. Here, we present structural, biochemical and molecular dynamics simulation studies on MiEH2, a plant epoxide hydrolase from Mangifera indica.

Brønsted Acid-Promoted Cyclodimerization of α,β-Unsaturated γ-Ketoesters: Construction of Fused Pyrano-ketal-lactones and γ-Ylidene-butenolides.

Unprecedented MsOH-promoted diastereoselective cascade dimerization and intramolecular lactonization of readily accessible α,β-unsaturated γ-ketoesters are presented. The results obtained in this work, control experiments, and density functional theory (DFT) calculations suggested that the initial enolization and to isomerization/equilibration of olefin (C=C) of substrate α,β-unsaturated γ-ketoesters give a -isomer preferentially over an -isomer. Subsequently, the -isomer undergoes intermolecular annulation with α,β-unsaturated γ-ketoesters via domino Michael addition/ketalization/lactonization steps to furnish fused tetracyclic pyrano-ketal-lactone.

Concise and collective total syntheses of 2,4-disubstituted furan-derived natural products from hydroxyoxetanyl ketones.

The furan moiety, prevalent in bioactive natural products and essential drugs, presents intriguing structural features that have spurred our exploration into streamlined chemical synthesis routes for related natural products. In this study, we demonstrate the concise total synthesis of eight 2,4-disubstituted furan-derived natural products (including methylfuroic acid, rabdoketones A and B, paleofurans A and B, tournefolin C, and shikonofurans A and B). Our methodology revolves around the utilization of hydroxyoxetanyl ketones as pivotal intermediates.

Divergent access to polycyclic spiro- and fused-,O-ketals through Bi(OTf)-catalyzed [4+2]-annulation of cyclic -sulfonyl ketimines and alkynols.

Bismuth(III) triflate-catalyzed [4+2]-annulation of cyclic -sulfonyl ketimines (derived from saccharin) and alkynyl alcohols (4-pentyn-1-ols and 5-hexyn-1-ols) has been reported. This cascade annulation provides a diverse array of polycyclic spiro-and-fused ,-ketals with excellent substrate scope, good isolated yields, and diastereoselectivities under mild reaction conditions.

Aminoacylase efficiently hydrolyses fatty acid amino acid conjugates of Helicoverpa armigera potentially to increase the pool of glutamine.

One of the most prevalent bioactive molecules present in the oral secretion (OS) of lepidopteran insects is fatty acid amino acid conjugates (FACs). Insect dietary components have influence on the synthesis and retaining the pool of FACs in the OS. We noted differential and diet-specific accumulation of FACs in the OS of Helicoverpa armigera by using Liquid Chromatography-Quadrupole Time of Flight Mass Spectrometry.

Bi(OTf)-promoted cascade annulation of hydroxy-pyranones and unsaturated γ-ketoesters for the construction of polycyclic bridged pyrano-furopyranones.

An efficient protocol for constructing complex three dimensional polycyclic bridged chromano-furopyranones and pyrano-furopyranones (closely related to bioactive natural products) bismuth(III)-catalyzed cascade annulation of hydroxy-pyranones and unsaturated γ-ketoesters is presented. This process involves intermolecular Michael addition, intramolecular hemiketalization, lactonization, formation of one C-C bond and two C-O bonds, rings, and contiguous stereocenters.

Regioselective Synthesis of Benzannulated [5,6]-Oxaspirolactones via Cu(II)-Catalyzed Cycloisomerization of 2-(5-Hydroxyalkynyl)benzoates.

Spiroketals and oxaspirolactones are widely found in biologically active natural products, serving as important structural motifs. In this study, we present a Cu(II)-catalyzed cascade cycloisomerization of 2-(5-hydroxyalkynyl)benzoates, enabling the regioselective synthesis of benzannulated [5,6]-oxaspirolactones containing an isochromen-1-one moiety. This strategy offers a rapid and efficient approach to access a diverse array of benzannulated [5,6]-oxaspirolactones.

Metabolites from subsp. : Isolation, Structure Elucidation, and Antimicrobial Activity.

Herein, we disclose the identification of novel metabolites from a potential probiotic strain, subsp. obtained from traditional dairy milk samples collected in Maharashtra, India (in January 2021). Isolated metabolites include pyrazin-2-carboxamide [, pyrazinamide, a potential antitubercular drug], 3,5-dihydroxy-6-methyl-2,3-dihydro-4-pyran-4-one (, DDMP), 2,4-di--butylphenol (), and hexadecanoic acid (, palmitic acid).

Divergent Synthesis of Oxepino-Phthalides and [5,5]-Oxaspirolactones through [2 + 2 + 2]- and [2 + 3]-Annulation of Alkynyl Alcohols with α-Ynone-Esters.

Unmasking the synthetic potential of alkyne functional group of alkynyl alcohols as surrogates of carbonyl compounds, herein we present the first Brønsted acid (TfOH)-catalyzed [2 + 2 + 2]-annulation of 4-pentyn-1-ols (possessing terminal alkyne) with α-ynone-esters to access tricyclic tetrahydro-oxepino-phthalides. Besides, an unprecedented synthesis of α-acetoaryl or α-alkynyl [5,5]-oxaspirolactones has been demonstrated by employing 4-pentyn-1-ols (possessing an internal alkyne) as an annulation partner, which proceeds through a divergent [2 + 3]-annulation pathway.

Bi(III)-Catalyzed Synthesis of Substituted Furans from Hydroxy-oxetanyl Ketones: Application to Unified Total Synthesis of Shikonofurans J, D, E, and C.

We report an improved synthetic protocol for hydroxy methyl-derived polysubstituted furans employing Bi(III)-catalyzed dehydrative cycloisomerization of α-hydroxy oxetanyl ketones. This procedure provides rapid access (within 5 min) to highly substituted furans with exceptional functional group diversity, excellent yields, generality, scalability, and operationally simple reaction conditions. Further, it demonstrated the utility of this method in the first enantioselective total synthesis of furyl-hydroquinone-derived biologically potent natural products shikonofurans J, D, E, and C in seven linear steps, starting from readily available building blocks of 2,5-dihydroxy acetophenone and 3-oxetanone employing chiral-phosphoric acid (TRIP)-catalyzed asymmetric prenylation as a key step to induce the chirality.

Concise Total Synthesis of (+)-Lanceolactone A: Revision of Absolute Stereochemistry.

A chiral-pool protecting-group-free five-step total synthesis of tetranorsesquiterpenoide (+)-lanceolactone A and all of its four stereoisomers using ()-(+)-, and ()-(-)-linalool (coriandrol) as building blocks is disclosed. The key steps involved in this synthetic route are regioselective ozonolysis, Au(I)-catalyzed cycloisomerization-induced construction of furan from alleneone, and dye-sensitized photo-oxidation (through O; singlet oxygen) of hydroxyalkyl-tethered furan to access oxaspirolactone. After a thorough evaluation of electronic circular dichroism (ECD) and optical rotation data of all possible stereoisomers, the absolute configuration of natural lanceolactone A at the C4 and C7 positions has been assigned as (+)-(4,7), which is an enantiomer to the initially proposed structure (+)-(4,7).

Enceleamycins A-C, Furo-Naphthoquinones from sp. MCC0218: Isolation, Structure Elucidation, and Antimicrobial Activity.

Three novel furo-naphthoquinones, enceleamycins A-C (-), and a new -hydroxypyrazinone acid () were identified from the strain sp. MCC 0218, isolated from a soil sample collected from the Western Ghats of India. Their chemical structure and absolute and relative configurations were established by 1D and 2D NMR spectroscopy, single-crystal X-ray crystallography, and high-resolution mass spectrometry.

Ready Access to Benzannulated [5,5]-Oxaspirolactones Using Au(III)-Catalyzed Cascade Cyclizations.

This work showcases an unprecedented Au(III)-catalyzed cascade cyclization of 2-(4-hydroxyalkynyl)benzoates to access benzannulated [5,5]-oxaspirolactones related to biologically active natural products. This reaction proceeds through an initial 5--dig mode of hydroalkoxylation of the alkynol segment to give the oxocarbenium species (via cyclic enol-ether) followed by the addition of carboxylate onto the oxocarbenium that delivers the oxaspirolactone scaffold. While testing this method's scope, we found that the steric and electronic environment of the hydroxyl group could alter the reaction pathway that delivers isochromenone through a competitive 6--dig mode of attack of the carboxylate onto the tethered alkyne.

Studies directed toward the synthesis of hedycoropyrans: total synthesis of des-hydroxy (-)-hedycoropyran B (-rhoiptelol B).

A full account of our efforts directed towards the synthesis of the diarylheptanoid-derived natural products hedycoropyrans that led to the total synthesis of -rhoiptelol B is described. In this endeavor, we have attempted two distinct synthetic strategies to access hedycoropyrans A and B, which led us to establish a facile synthetic route for des-hydroxy (-)-hedycoropyran B (-rhoiptelol B) from simple and readily accessible building blocks of 4-allylanisole and vanillin, employing Sharpless asymmetric epoxidation, CBS reduction, and an intramolecular AgOTf-catalyzed oxa-Michael reaction of suitably functionalized hydroxy-ynone as key transformations. The investigations disclosed herein will provide insights into designing novel synthetic routes for THP-DAH-derived natural products.

Stereoselective Total Synthesis of (±)-Pleurospiroketals A and B.

A full account of our efforts toward the stereoselective total synthesis of sesquiterpenoid-derived natural products (±)-pleurospiroketals A and B is described. Commercially available 3-methyl-2-cyclohexenone and 2,2-dimethyloxirane were used as key building blocks, and the substrate-controlled stereoselection was exploited to access the entire stereochemistry of these natural products. Initially, a planned synthetic route involving a [6,5]-bicyclic lactone intermediate was found to be insurmountable, and the later strategy comprising OsO-NMO-mediated dihydroxylation of 3-methyl-2-cyclohexenone, followed by Luche reduction, Eschenmoser methylenation, and Brønsted acid-induced spiroketalization steps, was ultimately identified as the reliable strategy.

Bismuth(III)-catalyzed bis-cyclization of propargylic diol-esters: a unified approach for the synthesis of [5,5]- and [6,5]-oxaspirolactones.

Herein we disclose an unprecedented intramolecular cascade strategy for the construction of α,β-unsaturated [5,5]- and [6,5]-oxaspirolactones that capitalizes on the π-electrophilic Lewis acid-catalyzed 5-exo-dig or 6-exo-dig mode of cyclization of propargylic diol esters, followed by dehydration and spirolactonization steps. Moreover, semi-protected substrates also delivered the respective oxaspirolactones with the same ease and in appreciable yields under optimal reaction conditions.

Total Synthesis of Beshanzuenone D and Its Epimers and Abiespiroside A.

A unified and protecting-group-free six-step total synthesis of bisabolane-type sesquiterpenoid beshanzuenone D and its stereoisomers and abiespiroside A using -(+)-carvone as a common chiral-pool building block is disclosed. This synthetic route features chemoselective allylic chlorination of carvone, Au(I)-catalyzed cycloisomerization induced construction of furan from homopropargylic diol, substrate-controlled selective hydroxylation using Davis-oxaziridine, and dye-sensitized photo-oxidation (through O) of hydroxyalkyl tethered furan to access oxaspirolactone as key transformations. A comprehensive set of NMR data along with DFT calculations, ECD spectra, and optical rotation measurements of the synthesized beshanzuenone D and its epimers were obtained to confirm absolute configurations.

Recent advances in the synthesis of oxaspirolactones and their application in the total synthesis of related natural products.

Oxaspirolactones are ubiquitous structural motifs found in natural products and synthetic molecules with a diverse biochemical and physicochemical profile, and represent a valuable target in natural product chemistry and medicinal chemistry. Since the 1970s, numerous innovative synthetic methodologies have been reported for these scaffolds in the context of expanding the range of potential building blocks, catalysts, and modes of transformations (racemic or asymmetric protocols). This review focuses on a broad spectrum of approaches toward the synthesis of oxaspirolactones and their potential application in the total synthesis of biologically relevant natural products starting from the first disclosure to the latest report.

Fe(III)-Catalyzed Diastereoselective Friedel-Crafts Alkylation-Hemiketalization-Lactonization Cascade for the Synthesis of Polycyclic Bridged 2-Chromanol Lactones.

An unprecedented Fe(III)-catalyzed Friedel-Crafts alkylation-hemiketalization-lactonization cascade of electron-rich hydroxy arenes and distinctively functionalized unsaturated 4-keto esters is developed for the construction of polycyclic bridged 2-chromanol lactones. Following this simple and facile protocol, a broad range of products was prepared in good to excellent yields as a single diastereomer. An unusual conglomerate (enantiomerically pure polymorph) of 3ac is reported along with the absolute stereochemistry, and the remaining products were rigorously confirmed by single-crystal X-ray analysis and analogy.

Four-Step Total Synthesis of (+)-Yaoshanenolides A and B.

A highly concise bioinspired four-step total synthesis of yaoshanenolides A and B possessing tricyclic spirolactone with an unusual 5'-spiro-[bicyclo[2.2.2]-oct[2]ene-7,2'-furan]-5'-one scaffold is reported.