Total Synthesis Research Articles

An Enabling Peptide Ligation Induced by Thiol-Salicylaldehyde Ester for Chemical Protein Synthesis.

Chemical protein synthesis by amide-forming ligation of two unprotected peptide segments offers an effective strategy for the preparation of protein derivatives that are not accessible through bioengineering approaches. Herein, an unprecedented chemical ligation between peptides with C-terminal 2-mercaptobenzaldehyde (thiol-salicylaldehyde, TSAL) esters and peptides bearing N-terminal cysteine/penicillamine is reported. Reactive peptide TSAL esters can be obtained from peptide hydrazides in an operationally simple and highly effective manner. This chemoselective peptide ligation enables the rapid production of N,S-benzylidene acetal intermediates, which can readily be converted into native amide bonds even at sterically hindered junctions. In addition, the current method can be applied compatibly in concert with other types of ligations and subsequent desulfurization chemistry, thereby facilitating convergent protein synthesis. The effectiveness of this new method is also showcased by the total synthesis of proteins ubiquitin and hyalomin-3 (Hyal-3), the efficient synthesis of protein ubiquitin-fold modifier 1 (UFM1) via a C-to-N sequential TSAL ester-induced ligation strategy, and the chemical synthesis of protein Mtb CM through a combined strategy of Ser/Thr ligation and TSAL ester-induced ligations.

Efficient Biomimetic Total Synthesis, Characterization, and Antioxidant Activity of Ommatins

Efficient Biomimetic Total Synthesis, Characterization, and Antioxidant Activity of Ommatins

Concise Synthesis and Biological Evaluation of the Pyrrolo[4,3,2-de]quinoline Core of the Lymphostin Family.

The efficient synthesis of the pyrrolo[4,3,2-de]quinoline core of the lymphostin family (compound 1) has been accomplished in 7 steps and 18.6% overall yield, providing an efficient method for the total synthesis and structural modification of the lymphostin family. Compound 1 showed potent inhibitory activities against PI3K/mTOR in the nanomolar range and activity against human colorectal cancer cell lines comparable to that of oxaliplatin, which could be recognized as a novel lead compound for cancer therapy.

Stereocontrolled Synthesis of 1,4-Dicarbonyls via [3,3]-Sulfonium Rearrangement and Application to the Synthesis of Heterocycles

Due to an inherent polarity mismatch of the corresponding retrosynthetic synthons, 1,4-dicarbonyl synthesis through polar pathways requires a retrosynthetic rethink. While Umpolung-based approaches exist, efficient control of both the absolute and relative configuration of newly formed stereogenic centres within this motif has long proven particularly challenging. In this Synpacts, we highlight our work on the stereodivergent synthesis of 1,4-dicarbonyl compounds through an unusual transformation that relies on vinyl sulfoxides and ynamides as reactants. This method allows stereoselective access to each and every one out of the four possible stereoisomers of a generic 1,4-dicarbonyl target in a process where enantio- and diastereoselectivity are “dialled into” the vinyl sulfoxide partner. Recent studies show that the thus formed 1,4-dicarbonyls serve as excellent linchpins for structural diversification into highly substituted heterocycles, including those found in natural products. 1. Introduction 2. Synthesis of 1,4-dicarbonyl compounds under acid catalysis 3. Cyclisation towards γ-lactones and γ-lactams 4. Application in total synthesis 5. Conclusion

Activity and Biocatalytic Potential of an Indolylamide Generating Thioesterase.

The chemical synthesis of N-acyl indoles is hindered by the poor nucleophilicity of indolic nitrogen, necessitating the use of strongly basic reaction conditions that encumber elaboration of highly functionalized scaffolds. Herein, we describe the total chemoenzymatic synthesis of the bulbiferamide natural products by the biochemical activity reconstitution of a nonribosomal peptide synthetase assembly line-derived (NRPS-derived) thioesterase that neatly installs the macrocyclizing indolylamide. The enzyme represents a starting point for biocatalytic access to macrocyclic indolylamide peptides and natural products.

Computation‐Guided Scope Exploration of a Conjugate Addition/Truce‐Smiles Cascade Reaction for Scaffold Diversification

Based on the successful application of a nitroaryl transfer cascade reaction in the total synthesis of various monoterpene indole alkaloids proceeding via fused bicyclic intermediate, we investigated analogous cascade reactions involving spiro, bridged, and alternatively fused bicyclic intermediates. Unfortunately, none of these was found to afford the desired nitroaryl transfer product. DFT studies of the original cascade process revealed that the Truce‐Smiles rearrangement is the rate‐determining step. In addition, we found that the subsequent SO2 extrusion is accompanied by retro‐Mannich ring opening, resulting in a stabilized enolate that only recyclizes after activation of the cyclic imine moiety. Computation of the reaction profiles of the proposed alternative cascade reactions showed that the barrier for the Truce‐Smiles rearrangement is unreasonably high for the bridged and alternatively fused systems, but only moderately higher for the five‐membered spiro system. Reasoning that even more electron‐deficient arenesulfonamides should have a lower barrier for the Truce‐Smiles rearrangement, we synthesized the corresponding 2,4‐dinitrobenzenesulfonamide precursor and found that it indeed smoothly undergoes the nitroaryl transfer cascade at room temperature. In this case, however, the cascade reaction produces a cyclic imine product, as the intermediate 2,4‐dinitrophenyl‐substituted enolate is insufficiently nucleophilic to undergo the Mannich cyclization.

Enantioselective Electrocatalysis for the Cross-Dehydrogenative Heteroarylation of Indoles, Pyrroles, and Furans.

Oxidative cross-dehydrogenative C-H/C-H functionalizations represent an exemplary approach for synthesizing carbonyl compounds via α-heteroarylation. Here we present the development of a direct anodic oxidative coupling process between 2-acylimidazoles and divergent heterocyclic systems including indole, pyrrole, and furan, facilitated by ferrocene-assisted asymmetric nickel electrocatalysis with high levels of enantioselectivity. Mechanistic investigations indicate that the reaction initially involves the formation of a chiral Ni-bound α-carbonyl radical, which is then captured by the heteroarene radical cation via intermolecular stereoselective radical/radical cation coupling. The mild, scalable, and robust reaction conditions allow for a broad substrate scope and excellent functional group tolerance, enabling access to a wide range of chiral hetero-compounds. The consequential α-heteroaromatic carbonyl products can potentially be transformed into a plethora of synthetically valuable frameworks, as exemplified by their application in the asymmetric total synthesis of (-)-COX-2 inhibitor, (+)-acremoauxin A, and (+)-pemedolac.

Enantioselective Electrocatalysis for the Cross‐Dehydrogenative Heteroarylation of Indoles, Pyrroles, and Furans

Oxidative cross‐dehydrogenative C‐H/C‐H functionalizations represent an exemplary approach for synthesizing carbonyl compounds via α‐heteroarylation. Here we present the development of a direct anodic oxidative coupling process between 2‐acylimidazoles and divergent heterocyclic systems including indole, pyrrole, and furan, facilitated by ferrocene‐assisted asymmetric nickel electrocatalysis with high levels of enantioselectivity. Mechanistic investigations indicate that the reaction initially involves the formation of a chiral Ni‐bound α‐carbonyl radical, which is then captured by the heteroarene radical cation via intermolecular stereoselective radical/radical cation coupling. The mild, scalable, and robust reaction conditions allow for a broad substrate scope and excellent functional group tolerance, enabling access to a wide range of chiral hetero‐compounds. The consequential α‐heteroaromatic carbonyl products can potentially be transformed into a plethora of synthetically valuable frameworks, as exemplified by their application in the asymmetric total synthesis of (‐)‐COX‐2 inhibitor, (+)‐acremoauxin A, and (+)‐pemedolac.

Total synthesis, stereochemical assignment, and biological evaluation of opantimycin A and analogues thereof.

Opantimycin A, a rare antimycin-class antibiotic without the macrolide core, was isolated from Streptomyces sp. RK88-1355 in 2017. In this study, we explored the total synthesis and stereochemical assignment of opantimycin A. The synthesis of all potential diastereomers has been accomplished via traceless Staudinger ligation. A comparison of the spectroscopic data of the synthesized compounds with that reported for the natural product confirmed that the absolute configuration of the natural product was (14S,17R,21R). Two analogous compounds were prepared, where the Dhb ((Z)-dehydrobutyrine) moiety was replaced with Dha (dehydroalanine) or ΔVal moieties, respectively. The inhibitory activities of these synthetic compounds against the production of the anti-inflammatory cytokine IL-6 were evaluated, and two potential candidates for further development as anti-inflammatory agents were identified.

Asymmetric Total Synthesis of Naturally Occurring (R)-2'-Methoxydihydroartemidin, (R)-(E)-3'-Hydroxyartemidin, and Its Structural Congeners: Method Optimization and Mechanistic Analysis.

Asymmetric total synthesis of naturally occurring 3-substituted isocoumarins, 2'-methoxydihydroartemidin, (E)-3'-hydroxyartemidin, and two structural congeners is reported in this article. Enantiopure 3-alkylisocoumarin core present in those target molecules was accessed through an atom-economical and regiodefined 6-endo-dig cyclization from properly substituted 2-halobenzoic acids and chiral terminal alkynes through ligand-free Cu(I) catalysis. A detailed mechanistic investigation was carried out through control experiments, and density functional theory (DFT) analysis reveals that solvent directed a non-Sonogashira pathway through direct insertion of alkyne through a regiodefined way is operating. The synthesized 3-alkylisocoumarins are synthetically manipulated into various small molecular entities.

Collective Asymmetric Synthesis of Thiosilvatins.

Thiosilvatins are a family of biologically active sulfenylated diketopiperazine natural products. The first members were reported over 40 years ago, but total synthesis of a thiosilvatin has remained elusive. Here, we describe the first, collective, synthesis of the parent epidithiodiketopiperazine (-)-dithiosilvatin and ten related thiosilvatins. Several of the targets are structurally revised. A catalytic asymmetric sulfenylation of triketopiperazines efficiently controls absolute configuration at the thioaminal units. Further synthetic highlights include a diastereoconvergent installation of the requisite cis-orientation of the sulfur atoms and a tandem epidisulfide formation/O-prenylation under mild Mitsunobu conditions. The described methods for late-stage diversification of sensitive bis(methylthio)diketopiperazines offer a blueprint for systematically exploring this interesting 3D-pharmacophore in stereochemically pure form.

Iriomoteolide-1a and -1b: Structure Elucidation by Integrating NMR Spectroscopic Analysis, Theoretical Calculation, and Total Synthesis.

The structure of iriomoteolide-1a, a marine macrolide with potent cytotoxic activity against human cancer cells, has been under scrutiny for more than a decade since the first total synthesis of the proposed structure was achieved by Horne. Here we disclose the correct structure of iriomoteolide-1a. Given a huge number of possible stereoisomers, we adopted an integrated strategy toward the structure elucidation of iriomoteolide-1a: (1) NMR spectroscopic analysis/molecular mechanics-based conformational analysis for configurational reassignment of the macrolactone domain; (2) model synthesis for validating the reassigned configuration of the macrolactone domain; (3) GIAO NMR calculation/DP4+ analysis of side chain stereoisomers; and (4) total synthesis of the most likely structure. Moreover, the correct structure of iriomoteolide-1b, a natural congener, was also determined by an integration of NMR spectroscopic analysis, GIAO NMR calculation/DP4+ analysis, and total synthesis.

4+1] Heteroannulation to Form 1‐Pyrrolines through Alder‐Ene Reaction of in situ Generated Ynimines: Development and Application in Total Synthesis of Borrecapine

AbstractWe report in this paper a novel Cu‐catalyzed synthesis of polysubstituted 1‐pyrrolines. The reaction of β,γ‐unsaturated oxime esters 4 with terminal alkynes 5 in the presence of a catalytic amount of Cu(OAc)2 and 2,2′‐biquinoline affords the corresponding 1,6‐enynimines, which undergo a highly stereoselective Alder‐ene reaction to afford 1‐pyrrolines with concomitant generation of a quaternary carbon and a 2‐azadiene motif. It represents an unusual [4+1] heteroannulation reaction wherein terminal alkynes act as a one carbon donor and are 1,1‐difunctionalized. Mechanistic studies suggest that the allylic hydrogen trans to the oxime ester main chain is selectively transferred to the electron‐rich alkyne during the pericyclic reaction. The resulting 1‐pyrrolines undergo facile acid‐catalyzed regioselective Wagner–Meerwein rearrangement to provide 2H‐pyrroles in excellent yields. The 2H‐pyrroles are also accessible from 4 and 5 in a one‐pot manner without isolation of the 1‐pyrrolines. Leveraging this heteroannulation reaction as a key step, the first total synthesis of borrecapine, a 2,3,3,5‐tetrasubstituted pyrrolidine, is accomplished.

Total Synthesis and Structural Reassignment of the Antitubercular Natural Product Evybactin.

The escalating threat posed by antibiotic resistance is a global concern and underscores the need for new antibiotics. In this context, the recent discovery of evybactin, a nonribosomal depsipeptide antibiotic that selectively and potently inhibits the growth of M. tuberculosis, is particularly noteworthy. Here, we present the first total synthesis of this natural product, along with a revision of its assigned structure. Our studies revealed a disparity between the structure originally proposed for evybactin and its actual configuration. Specifically, the 3-methylhistidine residue present in the evybactin core macrocycle was found to be of the d-configuration rather than the previously assigned l-His(Me). Having addressed this, we further optimized our solid-phase synthetic route to provide access to evybactin on a multi-hundred-milligram scale. Access to such quantities will allow for more comprehensive studies with this promising antibiotic.

Total Synthesis of (+)-Strepsesquitriol

Total Synthesis of (+)-Strepsesquitriol

Total Synthesis of (–)-Cyctetryptomycin A and B

Total Synthesis of (–)-Cyctetryptomycin A and B

Fe-Catalyzed α-C(sp3)-H Amination of N-Heterocycles.

Nitrogen-heterocycles are privileged structures in both marketed drugs and natural products. On the other hand, C-H amination reactions furnish unconventional and straightforward approaches for the construction of C-N bonds. Yet, most of the known methods rely on precious metal catalysts. Herein we report a site-selective intermolecular C(sp3)-H amination of N-heterocycles, catalyzed by inexpensive FeCl2,which allows the functionalization of a wide range of pharmaceutically relevant cyclic amines. The C-H amination occurs site-selectively in α-position to the nitrogen atom, even when weaker C-H bonds are present, and furnishes Troc-protected aminals or amidines. The method employs the N-heterocycle as limiting reagent and is applicable to the late-stage functionalization of complex molecules. Its synthetic potential was further illustrated through the derivatization of α-aminated products and the application to a concise total synthesis of the reported structure for senobtusin. Mechanistic studies allowed to propose a plausible reaction mechanism involving a turnover-limiting Fe-nitrene generation followed by fast H atom transfer and radical rebound.

Advances in the Synthesis of 3‐Acyl‐2‐Pyridones: Strategies and Methods for Accessing the Versatile Scaffold

ABSTRACTThe syntheses and bioevaluation of 3‐acyl‐2‐pyridones have garnered significant interest in recent years as a novel class of compounds with diverse biological activities. The bioactivities cover a wide range of therapeutic areas including antimicrobial, antitumor, anti‐inflammatory, antifungal, antibiotic, neuritogenic, cytotoxic, and antiviral activities. Therefore, 3‐acyl‐2‐pyridone scaffold offers a versatile platform for the development of new molecules with potential applications in medicinal chemistry. The recent exploration on synthesis and bioevaluation of 3‐acyl‐2‐pyridones has yielded promising results, making them attractive targets for further optimization and development of new therapeutic agents. This review summarizes the available information on total synthesis of 3‐acyl‐2‐pyridone containing natural products, and the other synthetic strategies developed for accessing the 3‐acyl pyridones such as multicomponent synthesis, condensation reaction, microwave‐assisted synthesis, catalytic hydrogenation reactions, metalation reaction, Michael addition, and formylation reactions. The presented information may serve as a valuable resource for researchers working in the field of medicinal chemistry and drug discovery, stimulating further exploration and development of this intriguing scaffold.

Total Synthesis of (–)-Euphordraculoate A and (+)-Pedrolide

Total Synthesis of (–)-Euphordraculoate A and (+)-Pedrolide

Fe‐Catalyzed α‐C(sp3)–H Amination of N‐Heterocycles

Nitrogen‐heterocycles are privileged structures in both marketed drugs and natural products. On the other hand, C–H amination reactions furnish unconventional and straightforward approaches for the construction of C–N bonds. Yet, most of the known methods rely on precious metal catalysts. Herein we report a site‐selective intermolecular C(sp3)–H amination of N‐heterocycles, catalyzed by inexpensive FeCl2, which allows the functionalization of a wide range of pharmaceutically relevant cyclic amines. The C–H amination occurs site‐selectively in α‐position to the nitrogen atom, even when weaker C–H bonds are present, and furnishes Troc‐protected aminals or amidines. The method employs the N‐heterocycle as limiting reagent and is applicable to the late‐stage functionalization of complex molecules. Its synthetic potential was further illustrated through the derivatization of α‐aminated products and the application to a concise total synthesis of the reported structure for senobtusin. Mechanistic studies allowed to propose a plausible reaction mechanism involving a turnover‐limiting Fe‐nitrene generation followed by fast H atom transfer and radical rebound.