Total Synthesis Research Articles

An Efficient and Scalable "Second Generation" Total Synthesis of the Marine Polyketide Limaol Endowed with Antiparasitic Activity.

The cluster of four skipped exo-methylene substituents on the "northern" wing of limaol renders this dinoflagellate-derived marine natural product unique in structural terms. This arguably non-thermodynamic array gains kinetic stability by virtue of populating local conformations which impede isomerization to a partly or fully conjugated polyene. This analysis suggested that the difficulties encountered during the late stages of our first total synthesis of this polyketide had not been caused by an overly fragile character of this unusual substructure; rather, an unfavorable steric microenvironment about the spirotricyclic core was identified as the likely cause. To remedy the issue, the protecting groups on this central fragment were changed; in effect, this amendment allowed all strategic and practical problems to be addressed. As a result, the overall yield over the longest linear sequence was multiplied by a factor of almost five and the material throughput increased more than eighty-fold per run. Key-to-success was a gold-catalyzed spirocyclization reaction; the reasons why a Brønsted acid cocatalyst is needed and the origin of the excellent levels of selectivity were delineated. The change of the protecting groups also allowed for much improved fragment coupling processes; most notably, the sequence of a substrate-controlled carbonyl addition reaction followed by Mitsunobu inversion that had originally been necessary to affix the southern tail to the core could be replaced by a reagent controlled asymmetric allylation. Finally, a much-improved route to the "northern" sector was established by leveraging the power of asymmetric hydrogenation of a 2-pyrone derivative. Limaol was found to combine appreciable antiparasitic activity with very modest cytotoxicity.

Asymmetric 1,2‐Migration at Vicinal Tetrasubstituted Stereocenters Constructed from α‐Keto Imines

AbstractA carbonyl‐assisted asymmetric 1,2‐migratory allylation through in situ generation of vicinal tetrasubstituted stereocenters is reported to access enantiopure α‐amino ketones and amino alcohols with excellent yields and diastereoselectivities. In a remarkable divergence, despite higher steric hindrance, the allylation exclusively occurs on ketones over imines in the first step, followed by a face‐selective 1,2‐allyl transfer, thus highlighting an exciting interplay between two distinct electrophiles. The methodology distinguishes itself through its adaptability to gram‐scale synthesis, showcasing broad functional‐group tolerance and stereodivergence. Density functional theory (DFT) analysis led to a deeper understanding of its selectivity and mechanistic framework. Highlighting its transformative potential, the method was applied to the total synthesis of hapalindole alkaloids.

Niosome-encapsulated auraptene reduced the mRNA expression of VEGF-A and PDGFs genes in human retina-derived RPE cell line.

To evaluate the effect of auraptene (AUR) treatment in forms of free and encapsulated in niosome nanoparticles by investigating the mRNA expression level of vascular endothelium growth factor (VEGF)-A and platelet-derived growth factors (PDGFs) in human retinal pigment epithelium (RPE) cell line. Niosome nanocarriers were produced using two surfactants Span 60 and Tween 80. RPE cell line was treated with both free AUR and niosome-encapsulated. Optimum dosage of treatments was calculated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Expression of VEGF-A and PDGF-A, PDGF-B, PDGF-C, PDGF-D genes was measured after total RNA extraction and cDNA synthesis, using real-time polymerase chain reaction (RT-PCR). The highest entrapment efficiency (EE) was achieved by Span 60:cholesterol (1:1) with 64.3%. The half maximal inhibitory concentration (IC50) of free and niosome-encapsulated AUR were 38.5 and 27.78 µg/mL, respectively. Release study revealed that niosomal AUR had more gradual delivery to the cells. RT-PCR results showed reduced expression levels of VEGF-A, PDGF-A, PDGF-B, PDGF-C, and PDGF-D after treatment with both free and niosomal AUR. Niosomal formulation of Span 60: cholesterol (1:1) is an effective drug delivery approach to transfer AUR to RPE cells. VEGF-A, PDGF-A, PDGF-B, PDGF-C, and PDGF-D are four angiogenic factors, inhibiting which by niosomal AUR may be effective in age-related macular degeneration.

Scalable Total Synthesis of Acremolactone B.

Acremolactone B is a pyridine-containing azaphilone-type polyketide. The first total synthesis of this molecule was achieved on a gram scale, based on an aza-6π electrocyclization-aromatization strategy for construction of the tetra-substituted pyridine ring. A bicyclic intermediate was expeditiously prepared by using [2+2] photocycloaddition and chemoselective Baeyer-Villiger oxidation, which was further elaborated to a densely substituted aza-triene. An electrocyclization-aromatization cascade was utilized to forge the tetracyclic core of this natural product, and the side chain was introduced through diastereoselective acylation and reduction.

Scalable Total Synthesis of Acremolactone B

AbstractAcremolactone B is a pyridine‐containing azaphilone‐type polyketide. The first total synthesis of this molecule was achieved on a gram scale, based on an aza‐6π electrocyclization–aromatization strategy for construction of the tetra‐substituted pyridine ring. A bicyclic intermediate was expeditiously prepared by using [2+2] photocycloaddition and chemoselective Baeyer–Villiger oxidation, which was further elaborated to a densely substituted aza‐triene. An electrocyclization–aromatization cascade was utilized to forge the tetracyclic core of this natural product, and the side chain was introduced through diastereoselective acylation and reduction.

Total Synthesis of (±)-Keramaphidin B and (±)-Ingenamine

Total Synthesis of (±)-Keramaphidin B and (±)-Ingenamine

First total synthesis of 2-deoxy-4′-thio-D-xyloside, a precursor for synthesis of D-2-deoxy-4′-thionucleosides

2-Deoxy-4′-thio-D-sugars are potential thiosugar donors for glycosylation reactions with nucleobases to produce various D-deoxy-4′-thionucleosides. However, thio-inversion reactions that produce D-deoxy-4′-thio-D-sugars depend on using a starting material, L-deoxysugar, which is expensive. Herein, we report a unique synthetic methodology to produce 2-deoxy-4′-thio-D-sugars using a D-sugar as an inexpensive starting material. Following our synthetic procedures for carbonyl translocation, d-ribose was transformed to 2-deoxy-l-ribosyl dithioacetal as a key intermediate. Mesylation and triflation provide the corresponding dialkylthio acetals as key precursors. Under thio-inversion reaction with iodide reagents, D-2-deoxy-4′-thioxyloside was successfully produced for the first time.

Abstract PR002: Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer

Abstract Despite the tremendous success of PARP1 inhibitors (PARPi) for the treatment of BRCA mut tumors, intrinsic and acquired resistance to PARPi remains a critical challenge in the clinic. This is, at least in part, due to the incomplete understanding of the mechanism of action (MoA) of PARPi. Recent studies from both our lab and others have pointed to PARP1 trapping as a key determinant of the anticancer effects of PARP1 inhibitors (PARPi). However, the molecular underpinnings of PARP1 trapping are poorly understood. Here we performed a proteomics-based chromatin relocalization screen, and identified RNF114, as a PARylation-dependent, E3 ubiquitin ligase involved in DNA damage response. Upon sensing genotoxicity, RNF114 was recruited, in a PAR-dependent manner, to DNA lesions, where it targeted PARP1 for degradation. The blockade of this pathway interfered with the removal of PARP1 from DNA lesions, leading to profound PARP1 trapping. A unique feature of this pathway is its druggability. We showed that a natural product, nimbolide, inhibited the E3 ligase activity of RNF114 and thus caused PARP1 trapping. However, unlike conventional PARPi, nimbolide treatment induced the trapping of both PARP1 and PARylation-dependent DNA repair factors. The unique mechaism of action of nimbolide translated into its superior cytotoxicity against BRCA mut cancer cells, compared to regular PARPi. It is also able to potentially overcome intrinsic and acquired resistance to PARPi, both in vitro and in vivo. In collaboration with Dr. Tian Qin, we recently performed the first total synthesis of nimbolide via a pharmacophore-directed, late-stage coupling strategy. Using this method, we have obtained a large panel of novel nimbolide analogs with improved activity and drug-like properties. We have further garnered key SAR (structure-activity relationship) insights into nimbolide. These results point to the exciting possibility of translating nimbolide analogs into novel PARP1-targeting agents for the treatment of BRCA mut cancers. Citation Format: Peng Li, Yuanli Zhen, Chiho Kim, Zhengshuai Liu, Jianwei Hao, Heping Deng, Hejun Deng, Min Zhou, Xu-Dong Wang, Tian Qin, Yonghao Yu. Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR002.

Asymmetric Total Synthesis of Lobophopyranone A and B

The first asymmetric total synthesis and structural confirmation of lobophopyranone A and B have been accomplished from commercially available starting materials. Reagent-controlled Keck-Maruoka allylation, Grignard reaction, chelation-controlled Sakurai allylation, and acid-mediated one-step TBS ether deprotection followed by cyclization are the crucial stages in this synthesis that create the 2,6-disubstituted dihydropyranone component.

Product Selectivity in Baeyer-Villiger Monooxygenase-Catalyzed Bacterial Alkaloid Core Structure Maturation.

Baeyer-Villiger monooxygenases (BVMOs) play crucial roles in the core-structure modification of natural products. They catalyze lactone formation by selective oxygen insertion into a carbon-carbon bond adjacent to a carbonyl group (Baeyer-Villiger oxidation, BVO). The homologous bacterial BVMOs, BraC and PxaB, thereby process bicyclic dihydroindolizinone substrates originating from a bimodular nonribosomal peptide synthetase (BraB or PxaA). While both enzymes initially catalyze the formation of oxazepine-dione intermediates following the identical mechanism, the final natural product spectrum diverges. For the pathway involving BraC, the exclusive formation of lipocyclocarbamates, the brabantamides, was reported. The pathway utilizing PxaB solely produces pyrrolizidine alkaloids, the pyrrolizixenamides. Surprisingly, replacing pxaB within the pyrrolizixenamide biosynthetic pathway by braC does not change the product spectrum to brabantamides. Factors controlling this product selectivity have remained elusive. In this study, we set out to solve this puzzle by combining the total synthesis of crucial pathway intermediates and anticipated products with in-depth functional in vitro studies on both recombinant BVMOs. This work shows that the joint oxazepine-dione intermediate initially formed by both BVMOs leads to pyrrolizixenamides upon nonenzymatic hydrolysis, decarboxylative ring contraction, and dehydration. Brabantamide biosynthesis is enzyme-controlled, with BraC efficiently transforming all the accepted substrates into its cognate final product scaffold. PxaB, in contrast, shows only considerable activity toward brabantamide formation for the substrate analog with a natural brabantamide-type side chain structure, revealing substrate-controlled product selectivity.

Circadian control of histone turnover during cardiac development and growth

During postnatal cardiac hypertrophy, cardiomyocytes undergo mitotic exit, relying on DNA replication-independent mechanisms of histone turnover to maintain chromatin organization and gene transcription. In other tissues, circadian oscillations in nucleosome occupancy influence clock-controlled gene expression, suggesting a role for the circadian clock in temporal control of histone turnover and coordinated cardiomyocyte gene expression. To elucidate roles for the master circadian transcription factor, Bmal1, in histone turnover, chromatin organization, and myocyte-specific gene expression and cell growth in the neonatal period. Bmal1 knockdown in neonatal rat ventricular myocytes (NRVM) decreased myocyte size, total cellular protein synthesis, and transcription of the fetal hypertrophic gene Nppb following treatment with serum or the α-adrenergic agonist phenylephrine (PE). Depletion of Bmal1 decreased expression of clock-controlled genes Per2 and Tcap, as well as Sik1, a Bmal1 target upregulated in adult versus embryonic hearts. Bmal1 knockdown impaired Per2 and Sik1 promoter accessibility as measured by MNase-qPCR and impaired histone turnover as measured by metabolic labeling of acid-soluble chromatin fractions. Sik1 knockdown in turn decreased myocyte size, while simultaneously inhibiting Nppb transcription and activating Per2 transcription. Linking these changes to chromatin remodeling, depletion of the replication-independent histone variant H3.3a inhibited myocyte hypertrophy and prevented PE-induced changes in clock-controlled gene transcription. Bmal1 is required for neonatal myocyte growth, replication-independent histone turnover, and chromatin organization at the Sik1 promoter. Sik1 represents a novel clock-controlled gene that coordinates myocyte growth with hypertrophic and clock-controlled gene transcription. Replication-independent histone turnover is required for transcriptional remodeling of clock-controlled genes in cardiac myocytes in response to growth stimuli.

Identification of Circular RNAs as Biomarker Candidates in Lung Cancer Treatment.

Lung cancer is the most common malignancy and among the leading cause of cancer death worldwide. Therefore, there is an important need for biomarkers that can be used in the early diagnosis of the disease and in the follow-up of treatment. Circular RNAs (circRNAs) have a covalently closed circular structure that lacks 3' and 5' polar ends and is resistant to RNAase enzymes. Due to these properties, they can be stably found in body fluids. Therefore, they can serve as potential biomarkers in the diagnosis, monitoring of therapeutic response and prognosis of cancer. In our study, we aimed to investigate the expression levels of circRNA molecules in the treatment of lung cancer and to determine those that have the potential to be biomarkers. In this in vitro study, expression levels of 163 circRNAs were investigated in A549 cells, a non-small cell lung cancer cell line, before and after treatment with carboplatin and pemetrexed. Total RNA isolation and cDNA synthesis were performed after treatments. Expression levels of circRNA genes were determined by RT-qPCR method with the designed divergent primer sequences. The study revealed the characterisation of differentially expressed circRNAs by treatment in lung cancer cells. Of them, hsa_circ_0001320 is not expressed in cancer cells, is expressed only after treatment, and increased the level of its expression in response to combination therapy. As a result, while carboplatin, pemetrexed, and combined drug applications changed the expression levels of some circRNAs in lung cancer cells, some circRNAs were expressed only after treatment. In treatment follow-up and management, hsa_circ_0001320 has been identified as potential biomarker candidate.

Total synthesis of all stereoisomers of C5- glyceryl-methyl-2′-deoxycytidine 5gmC and their occurrence in Chlamydomonas reinhardtii

Total synthesis of all stereoisomers of C5- glyceryl-methyl-2′-deoxycytidine 5gmC and their occurrence in Chlamydomonas reinhardtii

Evaluation of a cascade cyclization approach toward harringtonolide

An account of synthetic work directed toward the total synthesis of the cytotoxic cephalotaxus norditerpenoid, harringtonolide, is disclosed. An initial Lewis Acid-catalyzed Diels-Alder/Ene cascade was designed to construct a key 6,6,5-fused tricyclic building block in a single step. While this process could not be realized in a single pot, a three-step cycloaddition/Barbier-type sequence afforded this motif, and after subsequent ring-closing metathesis, the entire 7,6,6,5-fused core of the natural product was generated. This strategy could be of use in the synthesis of various cephalotane natural products containing 7-membered rings.

Enantioselective formal total synthesis of dihydrospirotryprostatin B

Spirotryprostatins are representative members of medicinally interesting bioactive molecules of the spirooxindole natural products. In this communication, we present a novel enantioselective total synthesis of the spirooxindole alkaloid dihydrospirotryprostatin B. The synthesis takes advantage of copper-catalyzed tandem reaction of o-iodoanilide chiral sulfinamide derivatives with alkynone to rapidly construct the key quaternary carbon stereocenter of the natural product dihydrospirotryprostatin B.

Organic Electrosynthesis: A Promising Green Tool in Solving Key Steps for the Total Synthesis of Complex Natural Products

Abstract: Electro-organic synthesis, an atom-efficient, sustainable, mild process, permits an ecofriendly and elegant green path to synthesize structurally complex, still valuable molecules, avoiding the use of conventional harsh oxidizing and reducing agents and long-route reaction protocols. Being one of the oldest forms of reaction setups in a laboratory, it deals with fundamental redox chemistry through the direct application of electrical potential. Here flow of electrons acts as an oxidizing agent at the anode at the same time reducing agent at the cathode, depending upon the requirement of the reaction. Simultaneously, it minimizes the generation of reagent waste during the reaction. However, electrifying organic synthesis plays more than preventing the waste footprint. This technology provides an alternative roadmap through nonclassical bond disconnections to access desired target molecules by cutting down a number of steps with the formation of apparently looking difficult bonds with excellent regio-, chemo-and stereoselectivity. Hence, it emerges as an alternative and attractive technique for the contemporary synthetic communities. Consequently, in recent years, multiple milestones have been achieved in the electro-organic synthesis of fascinating natural products through oxidative C-C bond formation, C-H/N-H functionalization, very rare oxidative N-N dimerization, RCDA dimerization, etc. Thus, synthesis of extremely complex natural products through finding new electro-synthetic route as a key methodology have become one of the alluring synthetic targets to synthetic chemists because of their versatile utilities in medicine, agriculture, food, and cosmetic industry. This review presents advances in electrochemistry in the total synthesis of 20 complex natural products reported since 2013. Enabling synthetic steps are analyzed alongside innate advantages as well as future prospects are speculated.

An alternative total synthesis of Greensporone C

A simple and efficient stereo selective synthesis of 14-membered Benzannulated macrolactone, Greensporone C has been accomplished in 6.2% overall yield from inexpensive and commercially available starting materials. This convergent synthesis employs Sharpless asymmetric dihydroxylation, Wittig olefination and Yamaguchi macrolactonization as the key steps.

Asymmetric Total Synthesis of Alstrostine G Utilizing a Catalytic Asymmetric Desymmetrization Strategy.

A highly effective enantioselective monobenzoylation of 1,3-diols has been developed for the synthesis of 1,1-disubstituted tetrahydro-β-carbolines. The chemistry has been successfully applied to the asymmetric total synthesis of (+)-alstrostine G, which also features a cascade Heck/hemiamination reaction enabling facile construction of the pivotal pentacyclic core.

Acceptor‐Reactivity‐Controlled Stereoconvergent Synthesis and Immunological Activity of a Unique Pentasaccharide from the Cell Wall Polysaccharide of Cutibacterium acnes C7

AbstractBacterial cell‐surface polysaccharides are involved in various biological processes and have attracted widespread attention as potential targets for developing carbohydrate‐based drugs. However, the accessibility to structurally well‐defined polysaccharide or related active oligosaccharide domains remains challenging. Herein, we describe an efficiently stereocontrolled approach for the first total synthesis of a unique pentasaccharide repeating unit containing four difficult‐to‐construct 1,2‐cis‐glycosidic linkages from the cell wall polysaccharide of Cutibacterium acnes C7. The features of our approach include: 1) acceptor‐reactivity‐controlled glycosylation to stereoselectively construct two challenging rare 1,2‐cis‐ManA2,3(NAc)2 (β‐2,3‐diacetamido‐2,3‐dideoxymannuronic acid) linkages, 2) combination use of 6‐O‐tert‐butyldiphenylsilyl (6‐O‐TBDPS)‐mediated steric shielding effect and ether solvent effect to stereoselectively install a 1,2‐cis‐glucosidic linkage, 3) bulky 4,6‐di‐O‐tert‐butylsilylene (DTBS)‐directed glycosylation to stereospecifically construct a 1,2‐cis‐galactosidic linkage, 4) stereoconvergent [2+2+1] and one‐pot chemoselective glycosylation to rapidly assemble the target pentasaccharide. Immunological activity tests suggest that the pentasaccharide can induce the production of proinflammatory cytokine TNF‐α in a dose‐dependent manner.

Acceptor-Reactivity-Controlled Stereoconvergent Synthesis and Immunological Activity of a Unique Pentasaccharide from the Cell Wall Polysaccharide of Cutibacterium acnes C7.

Bacterial cell-surface polysaccharides are involved in various biological processes and have attracted widespread attention as potential targets for developing carbohydrate-based drugs. However, the accessibility to structurally well-defined polysaccharide or related active oligosaccharide domains remains challenging. Herein, we describe an efficiently stereocontrolled approach for the first total synthesis of a unique pentasaccharide repeating unit containing four difficult-to-construct 1,2-cis-glycosidic linkages from the cell wall polysaccharide of Cutibacterium acnes C7. The features of our approach include: 1) acceptor-reactivity-controlled glycosylation to stereoselectively construct two challenging rare 1,2-cis-ManA2,3(NAc)2 (β-2,3-diacetamido-2,3-dideoxymannuronic acid) linkages, 2) combination use of 6-O-tert-butyldiphenylsilyl (6-O-TBDPS)-mediated steric shielding effect and ether solvent effect to stereoselectively install a 1,2-cis-glucosidic linkage, 3) bulky 4,6-di-O-tert-butylsilylene (DTBS)-directed glycosylation to stereospecifically construct a 1,2-cis-galactosidic linkage, 4) stereoconvergent [2+2+1] and one-pot chemoselective glycosylation to rapidly assemble the target pentasaccharide. Immunological activity tests suggest that the pentasaccharide can induce the production of proinflammatory cytokine TNF-α in a dose-dependent manner.