Atroposelective Total Synthesis of Cihunamide B.

A short, atroposelective synthesis of cihunamide B (1) is reported. The feature of this report is the decagram-scale SNAr reaction of l-tryptophan derivatives, followed by atroposelective Larock macrocyclization. This strategy allowed the construction of a Trp-Trp cross-linkage with unprecedented atropisomerism. The atroposelectivity of this Larock macrocyclization has been investigated through a combination of experimental and computational chemistry, yielding detailed insights into the synthesis of biaryl linkages. It also enabled the concise synthesis of cihunamide B (1), which is expected to be a potential antibacterial agent.

Short, Scalable Access to Pyrrovobasine.

A concise gram-scale synthesis of pyrrovobasine (1) is reported. Key transformations include a three-step decagram-scale synthesis of the tetracyclic compound, Mn-mediated direct radical cyclization, and the introduction of a naturally rare pyrraline structure. The synthesis is designed to be applicable to gram-scale synthesis using inexpensive and readily available reagents.

Atroposelective Total Synthesis of Darobactin A.

A concise, modular synthesis of the novel antibiotic darobactin A is disclosed. The synthesis successfully forges the hallmark strained macrocyclic ring systems in a sequential fashion. Key transformations include two atroposelective Larock-based macrocyclizations, one of which proceeds with exquisite regioselectivity despite bearing an unprotected alkyne. The synthesis is designed with medicinal chemistry considerations in mind, appending key portions of the molecule at a late stage. Requisite unnatural amino acid building blocks are easily prepared in an enantiopure form using C-H activation and decarboxylative cross-coupling tactics.

Two-Phase Synthesis of Taxol.

Taxol (a brand name for paclitaxel) is widely regarded as among the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically guided access to synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and eventual commercialization have relied upon natural (plant material) or biosynthetically derived (synthetic biology) supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of biosynthetic machinery for terpene synthesis can be used to arrive at Taxol.

Concise Construction of the ACDE Ring System of Calyciphylline†A Type Alkaloids by a [5+2] Cycloaddition.

A concise route for construction of the ACDE ring skeleton in calyciphylline A type alkaloids was developed using an intramolecular [5+2] cycloaddition reaction of an oxidopyrylium species bearing a tetrasubstituted olefin. Key to the success of this reaction was the combination of acid and base, which accelerated the construction of this skeleton containing a spiro ring and vicinal quaternary carbon centers. The resultant tricyclic ADE ring compound was converted to an ACDE ring model through C-H oxidation and an aza-Wittig reaction.

Total Synthesis of Caprazamycin A: Practical and Scalable Synthesis of syn-ß-Hydroxyamino Acids and Introduction of a Fatty Acid Side Chain to 1,4-Diazepanone.

The first total synthesis of caprazamycin A (1), a representative liponucleoside antibiotic, is described. Diastereoselective aldol reactions of aldehydes 12 and 25-27, derived from uridine, with diethyl isocyanomalonate 13 and phenylcarbamate 21 were investigated using thiourea catalysts 14 or bases to synthesize syn-ß-hydroxyamino acid derivatives. The 1,4-diazepanone core of 1 was constructed using a Mitsunobu reaction, and the fatty acid side chain was introduced using a stepwise sequence based on model studies. Notably, global deprotection was realized using palladium black and formic acid without hydrogenating the olefin in the uridine unit.

Electrochemically Driven, Ni-Catalyzed Aryl Amination: Scope, Mechanism, and Applications.

C-N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.

11-Step Total Synthesis of Teleocidins B-1-B-4.

A unified and modular approach to the teleocidin B family of natural products is presented that proceeds in 11 steps and features an array of interesting strategies and methods. Indolactam V, the known biosynthetic precursor to this family, was accessed through electrochemical amination, Cu-mediated aziridine opening, and a remarkable base-induced macrolactamization. Guided by a desire to minimize concession steps, the tactical combination of C-H borylation and a Sigman-Heck transform enabled the convergent, stereocontrolled synthesis of the teleocidins.

Electrochemical C(sp3)-H Fluorination.

A simple and robust method for electrochemical alkyl C-H fluorination is presented. Using a simple nitrate additive, a widely available fluorine source (Selectfluor), and carbon-based electrodes, a wide variety of activated and unactivated C-H bonds were converted to their C-F congeners. The scalability of the reaction was also demonstrated with a 100 gram preparation of fluorovaline.

Electrochemically Enabled, Nickel-Catalyzed Amination.

Along with amide bond formation, Suzuki cross-coupling, and reductive amination, the Buchwald-Hartwig-Ullmann-type amination of aryl halides stands as one of the most employed reactions in modern medicinal chemistry. The work herein demonstrates the potential of utilizing electrochemistry to provide a complementary avenue to access such critical bonds using an inexpensive nickel catalyst under mild reaction conditions. Of note is the scalability, functional-group tolerance, rapid rate, and the ability to employ a variety of aryl donors (Ar-Cl, Ar-Br, Ar-I, Ar-OTf), amine types (primary and secondary), and even alternative X-H donors (alcohols and amides).

Synthesis of CPZEN-45: Construction of the 1,4-Diazepin-2-one Core by the Cu-Catalyzed Intramolecular Amidation of a Vinyl Iodide.

CPZEN-45 was developed as an antibiotic against Mycobacterium tuberculosis by the chemical modification of caprazamycins. CPZEN-45 has been synthesized in this study by the Cu-catalyzed intramolecular amidation of a complex vinyl iodide precursor bearing uridine and sugar moieties with a secondary amide, allowing for the construction of its 1,4-diazepin-2-one core.

Total synthesis of (-)-caprazamycin A.

Caprazamycin A has significant antibacterial activity against Mycobacterium tuberculosis (TB). The first total synthesis is herein reported and features a) the scalable preparation of the syn-ß-hydroxy amino acid with a thiourea-catalyzed diastereoselective aldol reaction, b) construction of a diazepanone with an unstable fatty-acid side chain, and c) global deprotection with hydrogenation. This report provides a route for the synthesis of related liponucleoside antibiotics with fatty-acid side chains.

Direct nucleophilic addition to N-alkoxyamides.

While the synthesis of amide bonds is now one of the most reliable organic reactions, functionalization of amide carbonyl groups has been a long-standing issue due to their high stability. As an ongoing program aimed at practical transformation of amides, we developed a direct nucleophilic addition to N-alkoxyamides to access multisubstituted amines. The reaction enabled installation of two different functional groups to amide carbonyl groups in one pot. The N-alkoxy group played important roles in this reaction. First, it removed the requirement for an extra preactivation step prior to nucleophilic addition to activate inert amide carbonyl groups. Second, the N-alkoxy group formed a five-membered chelated complex after the first nucleophilic addition, resulting in suppression of an extra addition of the first nucleophile. While diisobutylaluminum hydride (DIBAL-H) and organolithium reagents were suitable as the first nucleophile, allylation, cyanation, and vinylation were possible in the second addition including inter- and intramolecular reactions. The yields were generally high, even in the synthesis of sterically hindered α-trisubstituted amines. The reaction exhibited wide substrate scope, including acyclic amides, five- and six-membered lactams, and macrolactams.