Synthetic Sequence Research Articles

Appendage- and Scaffold-Diverse Electrophilic and Photoreactive Probes for Integrated Phenotypic Screening-Target Identification Campaigns via a Minimalist Bifunctional Isocyanide.

One of the grand challenges in chemical biology is identifying a small-molecule modulator for all proteins within a proteome. To expand the variety and number of ligandable proteins for drug discovery, the objective of this study was to synthesize and evaluate the protein target profiles of electrophilic and photoreactive fully functionalized small-molecule probes (FFSMPs) featuring increased scaffold-, appendage-, and protein-reactive functional group (PRFG) diversity. FFSMPs contain: (1) a protein-binding motif, (2) an electrophilic or photoreactive PRFG for target protein capture, and (3) a terminal alkyne for click chemistry-based proteomic applications. These compounds can be directly applied in phenotypic screening programs to identify ligand-protein pairs in cells unbiasedly. Herein, we highlight 17 examples from 34 structurally diverse FFSMPs featuring five electrophiles, three photoreactive groups, and 15 chemical scaffolds. Essential to the synthesis of the FFSMPs was a new minimalist bifunctional isocyanide in an "isocyanide-based multicomponent reaction-Boc deprotection-arming" synthetic sequence. To the best of our knowledge, this is the first report concerning the preparation of appendage- and scaffold-diverse FFSMPs for integrated phenotypic screening-target identification campaigns with the ability to examine either electrophilic or photoreactive PRFGs. In contrast, the status quo for such studies has been appendage-diverse FFSMPs comprised of a single chemical scaffold and a single PRFG, which limits efficient target protein capture and/or chemical space sampling significantly in the quest for discovering new drug targets and/or compounds with novel mechanisms of action. Phenotypic screening of the electrophilic members of our library identified several FFSMPs with potent antiproliferative activity against MCF10CA1a breast cancer cells. One of these FFSMPs (Compound 4a) covalently targeted and potently inhibited protein disulfide isomerase A1 (PDIA1). This study supports the continued use of minimalist bifunctional isocyanides as valuable building blocks for preparing structurally diverse FFSMPs for integrated phenotypic screening-target identification campaigns.

Kalata B1 Enhances Temozolomide Toxicity to Glioblastoma Cells.

Glioblastoma (GBM) is the most aggressive cancer originating in the brain, but unfortunately combination treatments with resection, radiation, and chemotherapy are relatively ineffective. Therefore, novel methods of adjuvant therapy are critically needed. Cyclotides are plant-derived circular peptides that chemosensitize drug-resistant breast cancer to doxorubicin. We analyzed naturally occurring and synthetic cyclotides (Cycloviolacin O3, Cycloviolacin O19, natural Kalata B1, synthetic Kalata B1, and Vitri E) alone and in co-exposure treatments with the drug temozolomide (TMZ) in human glioblastoma cells. The cyclotides were identified by UPLC-PDA and HPLC-UV. The synthetic Kalata B1 sequence was verified with orbitrap LC-MS, and structural confirmation was provided by NMR spectroscopy. The cyclotides displayed dose-dependent cytotoxicity (IC50 values 2.4-21.1 µM) both alone and as chemosensitizers of U-87 MG and T 98 cells to TMZ. In fact, a 16-fold lower concentration of TMZ (100 µM) was needed for significant cytotoxicity in U-87 MG cells co-exposed to synthetic Kalata B (0.5 µM). Similarly, a 15-fold lower concentration of TMZ (75 µM) was required for a significant reduction in cell viability in T 98 cells co-exposed to synthetic Kalata B1 (0.25 µM). Kalata B1 remained stable in human serum stability assays. The data support the assertion that cyclotides may chemosensitize glioblastoma cells to TMZ.

Design and Synthesis of Out/Out, Out/In, and In/In Epoxides in Polycyclic Cage Frameworks

AbstractWe report a useful synthetic approach to assemble in/in epoxide, in/out epoxide, and out/out epoxide in cage systems using the Corey–Chaykovsky reaction and the Peterson olefination as key steps. In this regard, a variety of pentacycloundecane (PCUD) based cage compounds containing oxirane rings with diverse stereochemical disposition were synthesized via a simple synthetic sequence. Five cage diones were used for this purpose, and the starting cage diones were prepared with easily accessible starting materials such as 1,4-hydroquinone derivatives and cyclopentadiene. Here, we have used the Diels–Alder (DA) reaction, a [2+2] photocycloaddition, the Corey–Chaykovsky reaction, and the Peterson olefination as crucial steps to prepare the target molecules.

Potent and Selective Oxidatively Labile Ether‐Based Prodrugs through Late‐Stage Boronate Incorporation

AbstractThis manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug‐activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal‐mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl‐linked prodrugs while retaining the ability to release alcohols. We report the preparation of prodrug analogues of the natural products camptothecin and pederin from acetal precursors that serve as protecting groups in their synthetic sequences. The BAO acetal groups cleave in the presence of hydrogen peroxide to release the cytotoxic agents. The pederin‐based prodrug shows dramatically greater cytotoxicity than negative controls and outstanding selectivity and potency toward cancer cell lines in comparison to non‐cancerous cell lines. This late‐stage functionalization approach to prodrug synthesis should be applicable to numerous systems that can be accessed through chemoselective processes.

Potent and Selective Oxidatively Labile Ether-Based Prodrugs through Late-Stage Boronate Incorporation.

This manuscript describes a new strategy for prodrug synthesis in which a relatively inert ether group is introduced at an early stage in a synthetic sequence and functionalized in the final step to introduce a prodrug-activating group through a chemoselective process. Boryl allyloxy (BAO) ether groups are synthesized through several metal-mediated processes to form entities that are readily cleaved under oxidative conditions commonly found in cancer cells. The high cleavage propensity of the BAO group allows for ether cleavage, making these compounds substantially more hydrolytically stable in comparison to acyl-linked prodrugs while retaining the ability to release alcohols. We report the preparation of prodrug analogues of the natural products camptothecin and pederin from acetal precursors that serve as protecting groups in their synthetic sequences. The BAO acetal groups cleave in the presence of hydrogen peroxide to release the cytotoxic agents. The pederin-based prodrug shows dramatically greater cytotoxicity than negative controls and outstanding selectivity and potency toward cancer cell lines in comparison to non-cancerous cell lines. This late-stage functionalization approach to prodrug synthesis should be applicable to numerous systems that can be accessed through chemoselective processes.

Investigation of the impact of local properties of 3D data on the accuracy of block matching-based speckle tracking echocardiography

Abstract Introduction: Due to its simplicity, block-matching is a popular motion-tracking method used in speckle-tracking echocardiography. Improvement of its robustness and accuracy is thus of prime interest. Although it seems plausible that the quality of block matching-based tracking depends on the local properties of image data, and thus, it should be possible to assess in advance how well certain portions of the image data are suited for displacement estimation, the potential relationship has not been studied extensively. Material and methods: This study aimed to search for a relationship between selected features of echocardiographic data and the quality of local displacement estimation. The study used a 3D synthetic B-mode imaging sequence data with known ground truth. Frame-to-frame displacements were estimated for 9856 points in five different frame pairs with mean inter-frame displacements of 0.15, 0.87, 2, 3.02, and 3.84 mm. In each case, tracking errors were evaluated against thirteen grayscale image features, the displacement’s magnitudes, and the normalized cross-correlation (NCX) values. Additionally, a multi-variable regression model was applied to test the combined ability of the proposed features to predict tracking quality. Results: Median tracking error magnitudes were 0.06, 0.13, 0.28, 0.74, and 1.5 mm for each image pair. Weak correlation between errors and individual data features was found only in the case of 3 features: NCX (Pearson’s correlation coefficients in the range of −0.366 to −0.223), number of speckles within the kernel (−0.283, −0.282, and −0.214 for three lowest deformations) and mean of the 3D gradient (−0.252, −0.237 and −0.25). The regression model, however, provided significant prediction improvement with R2 exceeding 0.5. Conclusions: In conclusion, only a weak relationship between the individual investigated kernel features and tracking accuracy has been established, but their combined strength can be assessed as at least moderate.

Sequestration of Dyes from Water into Poly(α-Olefins) Using Polyisobutylene Sequestering Agents

Trace concentrations of dyes are often present in textile wastewater streams and present a serious environmental problem. Thus, these dyes must be removed from wastewater either by degradation or sequestration prior to discharge of the wastewater into the environment. Existing processes to remove these wastewater contaminants include the use of solid sorbents to sequester dyes or the use of biochemical or chemical methods of dye degradation. However, these processes typically generate their own waste products, are not necessarily rapid because of the low dye concentration, and often use expensive or non-recyclable sequestrants or reagents. This paper describes a simple, recyclable, liquid–liquid extraction scheme where ionic dyes can be sequestered into poly(α-olefin) (PAO) solvent systems. The partitioning of anionic and cationic dyes from water into PAOs is facilitated by ionic PAO-phase anchored sequestering agents that are readily prepared from commercially available vinyl-terminated polyisobutylene (PIB). This is accomplished by a sequence of reactions involving hydroboration/oxidation, conversion of an alcohol into an iodide, and conversion of the resulting primary alkyl iodide into a cationic nitrogen derivative. The products of this synthetic sequence are cationic nitrogen iodide salts which serve as anionic sequestrants that are soluble in PAO. These studies showed that the resulting series of cationic PIB-bound cationic sequestering agents facilitated efficient extraction of anionic, azo, phthalein, and sulfonephthalein dyes from water into a hydrocarbon PAO phase. Since the hydrocarbon PAO phase is completely immiscible with water and the PIB derivatives are also insoluble in water, neither the sequestration solvent nor the sequestrants contaminate wastewater. The effectiveness and efficiency of these sequestrations were assayed by UV–visible spectroscopy. These spectroscopic studies showed that extraction efficiencies were in most cases >99%. These studies also involved procedures that allowed for the regeneration and recycling of these PAO sequestration systems. This allowed us to recycle the PAO solvent system for at least 10 sequential batch extractions where we sequestered sodium salts of methyl red and 4′,5′-dichlorofluorescein dyes from water with extraction efficiencies of >99%. These studies also showed that a PIB-bound derivative of the sodium salt of 1,1,1-trifluoromethylpentane-2,4-dione could be prepared from a PIB-bound carboxylic acid ester by a Claisen-like reaction and that the sodium salt of this β-diketone could be used to sequester cationic dyes from water. This PIB-bound anion rapidly and efficiently extracted >99% of methylene blue, malachite green, and safranine O from water based on UV–visible and 1H NMR spectroscopic assays.

Synthesis of N-(3-Acyloxyacyl)glycines, Small Molecules with Potential Role in Gut Microbiome-Endocannabinoidome Communication.

The synthesis of some N-(3-acyloxyacyl)glycines, an interesting class of bioactive gut microbiota metabolites, is described. This procedure involves seven reaction steps using the commercially available Meldrum's acid to obtain highly pure products, in normal or deuterated form. The key point of the synthetic strategy was the use of commendamide t-butyl ester as a synthetic intermediate, a choice that allowed the removal of the protecting group at the end of the synthetic procedure without degrading of the other ester bond present in the molecule. The developed synthetic sequence is particularly simple, uses readily available reagents and involves a limited number of purifications by chromatographic column, with a reduction in the volume of solvent and energy used.

Concise Synthesis of Pseudane IX, Its N-Oxide, and Novel Carboxamide Analogs with Antibacterial Activity.

A four-step synthesis of the natural product pseudane IX, starting from 3-oxododecanoic acid phenylamide and including only one chromatographic purification, was accomplished with an overall yield of 52%. The same synthetic sequence, but with a controlled partial reduction of a nitro group in the penultimate intermediate, led to the N-oxide of pseudane IX (NQNO). A shortened three-step variation of the synthesis allowed for the preparation of novel carboxamide analogs of the natural product. An agar diffusion assay against six different bacterial strains revealed significant antibacterial activity of the novel analogs against S. aureus at a concentration of 100 µg/mL. One of the novel compounds showed a remarkably broad spectrum of antibacterial activity, comparable to that of the positive control NQNO.

Super-Resolution Ultrasound Imaging Using the Erythrocytes-Part I: Density Images.

A new approach for vascular super-resolution (SR) imaging using the erythrocytes as targets (SUper-Resolution ultrasound imaging of Erythrocytes (SURE) imaging) is described and investigated. SURE imaging does not require fragile contrast agent bubbles, making it possible to use the maximum allowable mechanical index (MI) for ultrasound scanning for an increased penetration depth. A synthetic aperture (SA) ultrasound sequence was employed with 12 virtual sources (VSs) using a 10-MHz GE L8-18i-D linear array hockey stick probe. The axial resolution was [Formula: see text]m) and the lateral resolution was [Formula: see text]m). Field IIpro simulations were conducted on 12.5- μ m radius vessel pairs with varying separations. A vessel pair with a separation of 70 μ m could be resolved, indicating a SURE image resolution below half a wavelength. A Verasonics research scanner was used for the in vivo experiments to scan the kidneys of Sprague-Dawley rats for up to 46 s to visualize their microvasculature by processing from 0.1 up to 45 s of data for SURE imaging and for 46.8 s for SR imaging with a SonoVue contrast agent. Afterward, the renal vasculature was filled with the ex vivo micro-computed tomography (CT) contrast agent Microfil, excised, and scanned in a micro-CT scanner at both a 22.6- μ m voxel size for 11 h and for 20 h in a 5- μ m voxel size for validating the SURE images. Comparing the SURE and micro-CT images revealed that vessels with a diameter of 28 μ m, five times smaller than the ultrasound wavelength, could be detected, and the dense grid of microvessels in the full kidney was shown for scan times between 1 and 10 s. The vessel structure in the cortex was also similar to the SURE and SR images. Fourier ring correlation (FRC) indicated a resolution capability of 29 μ m. SURE images are acquired in seconds rather than minutes without any patient preparation or contrast injection, making the method translatable to clinical use.

Non-contrast magnetic resonance evaluation of active multiple sclerosis lesions: Emerging role of quantitative synthetic magnetic resonance imaging.

The current study aims to explore the utility of novel synthetic MRI-derived quantitative parameters including myelin-correlated volume (MyC) in identifying active MS lesions without injecting gadolinium contrast. 43 MS patients underwent institutional MS protocol including 3D FLAIR and post-contrast 3D T1VIBE sequence on a 1.5T MR Scanner in addition to synthetic MRI sequence. MS plaques were categorised into enhancing (C) and non-enhancing (N) lesions. They were also sub-categorised based on location into periventricular WM lesions (P), deep WM lesions (D), infratentorial lesions (I) and cortical-juxtacortical (C) lesions. ROIs were placed on Synthetic FLAIR images in MS lesions and quantitative parameters of R1, R2, PD and myelin-correlated volume (MyC) obtained. Sensitivity and specificity for various cut-off values to differentiate enhancing from non-enhancing multiple sclerosis lesions were calculated by performing ROC curve analysis and logistic regression analysis. Contrast enhancing lesions demonstrated significantly higher mean R1, R2 values and lower mean PD values in comparison to non-enhancing lesions (p < 0.05) but with limited specificity. Region-wise analysis revealed high AUC values for mean R1 and R2 at cortical-juxtacortical lesions (p < 0.001) followed by periventricular lesions (p < 0.003) for differentiating enhancing from non-enhancing lesions with no significant contribution from MyC and PD values. Synthetic MRI-derived quantitative parameters of mean R1, R2, MyC and PD hold value in differentiating contrast enhancing and non-enhancing MS lesions without administering gadolinium-based contrast agent. However, the current study did not achieve significant specificity for establishing the same.

Diastereoselective Palladaelectro-Catalyzed Construction of Bromomethyl Morpholines as Key Step To Access Morpholino Homonucleosides.

A synthetic protocol for the preparation of a new class of morpholino homonucleosides in enantiopure form starting from readily available 1,2-aminoalcohols or glycidol has been developed. Key intermediates of the synthetic sequence are 2-bromomethyl morpholines, diastereoselectively achieved from the corresponding alkenols by palladaelectro-catalyzed alkoxybromination of unactivated alkenes. The so obtained bromo derivatives are in turn susceptible to functionalization with nucleic bases for easy access to morpholino homonucleosides.

Synthesis of 1-aryl-2,3-diaroyl cyclopropanes from 1,3,5-triaryl-1,5-diketones and their transformation into E,E-1,4-diaryl-1,3-butadienes.

A new method for the synthesis of 1-aryl-2,3-diaroyl cyclopropanes has been developed by iodine/DBU-mediated cyclization of 1,3,5-triaryl-1,5-diketones. The alcohols derived by the reduction of these cyclopropanes, when treated with conc. HCl, afforded a series of 1,3-dienes through cyclopropyl ring-opening and subsequent fragmentation. Overall, the synthetic sequence represents a new non-Wittig methodology for the synthesis of 1,3-dienes from 1,5-diketones.

Bioinformatic Prediction and High Throughput In Vivo Screening to Identify Cis-Regulatory Elements for the Development of Algal Synthetic Promoters.

Algae biotechnology holds immense promise for revolutionizing the bioeconomy through the sustainable and scalable production of various bioproducts. However, their development has been hindered by the lack of advanced genetic tools. This study introduces a synthetic biology approach to develop such tools, focusing on the construction and testing of synthetic promoters. By analyzing conserved DNA motifs within the promoter regions of highly expressed genes across six different algal species, we identified cis-regulatory elements (CREs) associated with high transcriptional activity. Combining the algorithms POWRS, STREME, and PhyloGibbs, we predicted 1511 CREs and inserted them into a minimal synthetic promoter sequence in 1, 2, or 3 copies, resulting in 4533 distinct synthetic promoters. These promoters were evaluated in vivo for their capacity to drive the expression of a transgene in a high-throughput manner through next-generation sequencing post antibiotic selection and fluorescence-activated cell sorting. To validate our approach, we sequenced hundreds of transgenic lines showing high levels of GFP expression. Further, we individually tested 14 identified promoters, revealing substantial increases in GFP expression─up to nine times higher than the baseline synthetic promoter, with five matching or even surpassing the performance of the native AR1 promoter. As a result of this study, we identified a catalog of CREs that can now be used to build superior synthetic algal promoters. More importantly, here we present a validated pipeline to generate building blocks for innovative synthetic genetic tools applicable to any algal species with a sequenced genome and transcriptome data set.

Electrochemical synthesis of peptide aldehydes via C‒N bond cleavage of cyclic amines

Peptide aldehydes are crucial biomolecules essential to various biological systems, driving a continuous demand for efficient synthesis methods. Herein, we develop a metal-free, facile, and biocompatible strategy for direct electrochemical synthesis of unnatural peptide aldehydes. This electro-oxidative approach enabled a step- and atom-economical ring-opening via C‒N bond cleavage, allowing for homoproline-specific peptide diversification and expansion of substrate scope to include amides, esters, and cyclic amines of various sizes. The remarkable efficacy of the electro-synthetic protocol set the stage for the efficient modification and assembly of linear and macrocyclic peptides using a concise synthetic sequence with racemization-free conditions. Moreover, the combination of experiments and density functional theory (DFT) calculations indicates that different N-acyl groups play a decisive role in the reaction activity.

Triindenotriphenylenes: Spin-Frustrated Triskelion Triradicals with Excellent Ambient Stability.

A triskelion-shaped triradical triindeno[1,2-a:1',2'-g : 1'',2''-m]triphenylen-7-yl (1) and its internally fused derivative (2) obtained by oxidative cyclization were prepared in a straightforward synthetic sequence. Both compounds were confirmed to be triradicals and to possess intramolecular antiferromagnetic exchange interactions between spins, displaying a spin-frustrated doublet ground state with doublet-quartet energy gaps of -0.14 kcal/mol for 1 and -0.06 kcal/mol for 2. Despite their open-shell character, they were sufficiently stable to be handled under ambient conditions on a timescale of days. Both compounds could be reversibly reduced to mono-, di-, and trianions and oxidized to 1+ and 22+, with strong NIR absorptions (1800 to over 3200 nm) observed for all open-shell ions.

Triindenotriphenylenes: Spin‐Frustrated Triskelion Triradicals with Excellent Ambient Stability

A triskelion‐shaped triradical triindeno[1,2‐a:1',2'‐g:1'',2''‐m]triphenylen‐7‐yl (1) and its internally fused derivative obtained by oxidative cyclization (2) were prepared in a straightforward synthetic sequence. Both compounds were confirmed to be triradicals and to possess intramolecular antiferromagnetic exchange interactions between spins, displaying a spin‐frustrated doublet ground state with doublet‐quartet energy gaps of −0.14 kcal/mol for 1 and −0.06 kcal/mol for 2. Despite their open‐shell character, they were sufficiently stable to be handled under ambient conditions on a timescale of days. Both compounds could be reversibly reduced to mono‐, di‐, and trianions and oxidized to 1+ and 22+, with strong NIR absorptions (1800 to over 3200 nm) observed for all open‐shell ions.

Novel neuroprotective 5,6-dihydropyrido[2′,1':2,3]imidazo[4,5-c]quinoline derivatives acting through cholinesterase inhibition and CB2 signaling modulation

A novel group of 5,6-dihydropyrido [2′,1':2,3]imidazo [4,5-c]quinolines was prepared via a microwave assisted one-pot telescopic approach. The synthetic sequence involves the formation of an amine precursor of imidazo [1,2-a]pyridine via condensation and reduction under microwave irradiation. Subsequently, the Pictet-Spengler cyclisation reaction occurs with ketones (cyclic or acyclic) to obtain substituted 5,6-dihydropyrido [2′,1':2,3]imidazo [4,5-c]quinolines in excellent yields. The compounds were tested as neuroprotective agents. Observed protection of neuron-like cells, SH-SY5Y differentiated with ATRA, in Parkinson's and Huntington's disease models inspired further mechanistic studies of protective activity against damage induced by 1-methyl-4-phenylpyridinium (MPP+), a compound causing Parkinson's disease. The novel compounds exhibit similar or higher potency than ebselen, an established drug with antioxidant activity, in the cells against MPP + -induced total cellular superoxide production and cell death. However, they exhibit a significantly higher capacity to reduce mitochondrial superoxide and preserve mitochondrial membrane potential. We also observed marked differences between a selected derivative and ebselen in terms of normalizing MPP + -induced phosphorylation of Akt and ERK1/2. The cytoprotective activity was abrogated when signaling through cannabinoid receptor CB2 was blocked. The compounds also inhibit both acetylcholine and butyrylcholine esterases. Overall the data show that novel 5,6-dihydropyrido [2′,1':2,3]imidazo [4,5-c]quinoline have a broad cytoprotective activity which is mediated by several mechanisms including mitoprotection.

Efficient and novel biosynthesis of myricetin α-triglucoside with improved solubility using amylosucrase from Deinococcus deserti

Although myricetin (3,3′,4′,5,5′,7-hexahydroxyflavone, MYR) has a high antioxidant capacity and health functions, its use as a functional food material is limited owing to its low stability and water solubility. Amylosucrase (ASase) is capable of biosynthesizing flavonol α-glycoside using flavonols as acceptor molecules and sucrose as a donor molecule. Here, ASase from Deinococcus deserti (DdAS) efficiently biosynthesizes a novel MYR α-triglucoside (MYRαG3) using MYR as the acceptor molecule. Comparative homology analysis and computational simulation revealed that DdAS has a different active pocket for the transglycosylation reaction. DdAS produced MYRαG3 with a conversion efficiency of 67.4 % using 10 mM MYR and 50 mM sucrose as acceptor and donor molecules, respectively. The structure of MYRαG3 was identified as MYR 4′-O-4″,6″-tri-O-α-D-glucopyranoside using NMR and LC-MS. In silico analysis confirmed that DdAS has a distinct active pocket compared to other ASases. In addition, molecular docking simulations predicted the synthetic sequence of MYRαG3. Furthermore, MYRαG3 showed a similar DPPH radical scavenging activity of 49 %, comparable to MYR, but with significantly higher water solubility, which increased from 0.03 μg/mL to 511.5 mg/mL. In conclusion, this study demonstrated the efficient biosynthesis of a novel MYRαG3 using DdAS and highlighted the potential of MYRαG3 as a functional material.

Synthesis of p-phenylene-based chiral dicarboxamides via aminocarbonylation of 1’,4-diiodostyrene

Chiral p-phenylene-based dicarboxamides featuring carboxamide and 2-arylacrylamide motifs were synthesised through a synthetic sequence involving conventional organic reactions followed by palladium-catalysed aminocarbonylation. 4-Iodoacetophenone was used as starting material to prepare to 1’,4-diiodostyrene, which underwent several aminocarbonylation reactions, using in situ formed palladium-phosphine catalysts and various biologically relevant amines as N-nucleophiles such as, amino acid esters, nortropine, and aminoandrostane derivatives. By exploring the remarkable difference in reactivity between the iodoalkene and iodoarene functionalities, the aminocarbonylation of the iodoalkene moiety was carried first with high chemoselectivity, followed by sequential transformation of the iodoarene functionality into the corresponding carboxamide using a different nucleophile. This approach allowed us to obtain a range of otherwise challenging chiral dicarboxamides, in moderate to high isolated yields through highly chemoselective reactions.