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Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine. A natural approach to natural product synthesis By combining two biosynthetic principles that have evolved in the natural world, David MacMillan and colleagues at the Merck Center for Catalysis at Princeton University, New Jersey, have developed a powerful strategy for the production of a broad spectrum of natural products. The first technique is organocascade catalysis, in which a continuous catalytic cascade replaces the traditional stop-go method of synthesis. The second is collective synthesis, in which a general synthetic route is used to reach a common molecular scaffold that, with appropriate fine-tuning, serves as a conduit to other members of the same chemical family. The method is demonstrated with the asymmetric total syntheses of six high-profile alkaloids: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.

Many natural products that contain basic nitrogen atoms—for example alkaloids like morphine and quinine—have the potential to treat a broad range of human diseases. However, the presence of a nitrogen atom in a target molecule can complicate its chemical synthesis because of the basicity of nitrogen atoms and their susceptibility to oxidation. Obtaining such compounds by chemical synthesis can be further complicated by the presence of multiple nitrogen atoms, but it can be done by the selective introduction and removal of functional groups that mitigate basicity. Here we use such a strategy to complete the chemical syntheses of citrinalin B and cyclopiamine B. The chemical connections that have been realized as a result of these syntheses, in addition to the isolation of both 17-hydroxycitrinalin B and citrinalin C (which contains a bicyclo[2.2.2]diazaoctane structural unit) through carbon-13 feeding studies, support the existence of a common bicyclo[2.2.2]diazaoctane-containing biogenetic precursor to these compounds, as has been proposed previously. Natural products citrinalin B and cyclopiamine B, which contain basic nitrogen atoms that are susceptible to oxidation during synthesis, can be synthesized by the selective introduction and removal of functional groups. Novel nitrogen-containing natural products synthesized This paper reports the first syntheses of the natural products citrinalin B and cyclopiamine B. And as a by-product of this work, the authors propose a revision of the structure initially assigned to citrinalin B. The presence of nitrogen atoms in a target molecule can complicate its synthesis because of nitrogen's basicity and susceptibility to oxidation. This can be circumvented by the selective introduction and removal of functional groups that mitigate basicity. The prenylated indole alkaloids citrinalin B and cyclopiamine B were produced using a refinement of the technique, opening up a class of compounds that includes therapeutics such as quinine and morphine to synthetic chemistry.

Canthin-6-one alkaloids have consistently attracted the interest of medicinal chemists due to their wide range of promising bioactivities, including antitumor, antifungal, antibacterial, and antiviral properties. However, their low natural abundance in plants has constrained the further exploration of their potential bioactivities. This study reports a comprehensive synthesis of canthin-6-one alkaloids, utilizing key Suzuki coupling and Cu-catalyzed amidation reactions to construct their core scaffold. Derivatives were synthesized with Koenig–Knorr glycosylation for the further modification of synthetic canthin-6-ones. The antimicrobial activities of the synthesized compounds were evaluated against C. albicans, C. neoformans, S. aureus and E. coli using the micro-dilution method. In total, 17 compounds were synthesized, including nine canthin-6-ones. Notably, alkaloids 4, 5, 7 and 12-13 were prepared for the first time, along with 8 new derivatives. Their structures were confirmed by NMR and MS analyses. At 50 µg/mL, the alkaloids 1-4 and 9 exhibited antimicrobial properties against C. albicans, C. neoformans and S. aureus. The antimicrobial activity of alkaloids 2, 4-5 and 12-13 against these four microbial human pathogens is reported here for the first time. Overall, this research not only advances our understanding of canthin-6-one alkaloid synthesis, but also provides a foundation for developing novel compounds with pharmaceutical properties.

Training algorithms to computationally plan multistep organic syntheses has been a challenge for more than 50 years 1 – 7 . However, the field has progressed greatly since the development of early programs such as LHASA 1 , 7 , for which reaction choices at each step were made by human operators. Multiple software platforms 6 , 8 – 14 are now capable of completely autonomous planning. But these programs ‘think’ only one step at a time and have so far been limited to relatively simple targets, the syntheses of which could arguably be designed by human chemists within minutes, without the help of a computer. Furthermore, no algorithm has yet been able to design plausible routes to complex natural products, for which much more far-sighted, multistep planning is necessary 15 , 16 and closely related literature precedents cannot be relied on. Here we demonstrate that such computational synthesis planning is possible, provided that the program’s knowledge of organic chemistry and data-based artificial intelligence routines are augmented with causal relationships 17 , 18 , allowing it to ‘strategize’ over multiple synthetic steps. Using a Turing-like test administered to synthesis experts, we show that the routes designed by such a program are largely indistinguishable from those designed by humans. We also successfully validated three computer-designed syntheses of natural products in the laboratory. Taken together, these results indicate that expert-level automated synthetic planning is feasible, pending continued improvements to the reaction knowledge base and further code optimization. A synthetic route-planning algorithm, augmented with causal relationships that allow it to strategize over multiple steps, can design complex natural-product syntheses that are indistinguishable from those designed by human experts.

Plants synthesize numerous alkaloids that mimic animal neurotransmitters 1 . The diversity of alkaloid structures is achieved through the generation and tailoring of unique carbon scaffolds 2 , 3 , yet many neuroactive alkaloids belong to a scaffold class for which no biosynthetic route or enzyme catalyst is known. By studying highly coordinated, tissue-specific gene expression in plants that produce neuroactive Lycopodium alkaloids 4 , we identified an unexpected enzyme class for alkaloid biosynthesis: neofunctionalized α-carbonic anhydrases (CAHs). We show that three CAH-like (CAL) proteins are required in the biosynthetic route to a key precursor of the Lycopodium alkaloids by catalysing a stereospecific Mannich-like condensation and subsequent bicyclic scaffold generation. Also, we describe a series of scaffold tailoring steps that generate the optimized acetylcholinesterase inhibition activity of huperzine A 5 . Our findings suggest a broader involvement of CAH-like enzymes in specialized metabolism and demonstrate how successive scaffold tailoring can drive potency against a neurological protein target. We show how neuroactive alkaloids from clubmosses are biosynthesized, which reveals an unexpected role for carbonic anhydrase-like enzymes in alkaloid scaffold formation.

The fungal-derived bicyclo[2.2.2]diazaoctane alkaloids are of interest to the scientific community for their potent and varied biological activities. Within this large and diverse family of natural products, the insecticidal metabolite (+)-brevianamide A is particularly noteworthy for its synthetic intractability and inexplicable biogenesis. Despite five decades of research, this alkaloid has remained an elusive target for chemical synthesis due to insurmountable issues of reactivity and selectivity associated with all previously explored strategies. We herein report the chemical synthesis of (+)-brevianamide A (seven steps, 7.2% overall yield, 750 mg scale), which involves a bioinspired cascade transformation of the linearly fused (−)-dehydrobrevianamide E into the topologically complex bridged-spiro-fused structure of (+)-brevianamide A.Despite five decades of research, the alkaloid (+)-brevianamide A has remained an elusive target for chemical synthesis. Now, it has been shown that the total synthesis of (+)-brevianamide A can be achieved in seven steps and 7.2% overall yield to give 750 mg of the target compound.

Enantiomerically enriched indole-containing heterocycles play a vital role in bioscience, medicine, and chemistry. As one of the most attractive subtypes of indole alkaloids, highly substituted tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. However, the syntheses of tetrahydro-γ-carbolines with high functionalities from readily available reagents are significant challenging. In particular, the stereodivergent syntheses of tetrahydro-γ-carbolines containing multi-stereogenic centers remain quite difficult. Herein, we report an expedient and stereodivergent assembly of tetrahydro-γ-carbolines with remarkably high levels of stereoselective control in an efficient cascade process from aldimine esters and indolyl allylic carbonates via a synergistic Cu/Ir catalyst system. Control experiments-guided optimization of synergistic catalysts and mechanistic investigations reveal that a stereodivergent allylation reaction and a subsequent highly stereoselective iso -Pictet-Spengler cyclization are the key elements to success. Tetrahydro-γ-carbolines are the basic structural unit in many natural products and pharmaceuticals. Here, the authors report a synergistic Cu/Ir system to assemble chiral tetrahydro-γ-carbolines via a stereodivergent allylation followed by a stereoselective iso-Pictet-Spengler cyclization.

The development of efficient methods, particularly catalytic and enantioselective processes, for the construction of all-carbon quaternary stereocentres is an important (and difficult) challenge in organic synthesis due to the occurrence of this motif in a range of bioactive molecules. One conceptually straightforward and potentially versatile approach is the catalytic enantioconvergent substitution reaction of a readily available racemic tertiary alkyl electrophile by an organometallic nucleophile; however, examples of such processes are rare. Here we demonstrate that a nickel-based chiral catalyst achieves enantioconvergent couplings of a variety of tertiary electrophiles (cyclic and acyclic α-halocarbonyl compounds) with alkenylmetal nucleophiles to form quaternary stereocentres with good yield and enantioselectivity under mild conditions in the presence of a range of functional groups. These couplings, which probably proceed via a radical pathway, provide access to an array of useful families of organic compounds, including intermediates in the total synthesis of two natural products, (–)-eburnamonine and madindoline A.A wide variety of bioactive molecules contain stereogenic quaternary carbons, and developing methods for the construction of these stereocentres continues to be an active area of research. Now, it has been shown that a nickel-catalysed enantioconvergent coupling of tertiary alkyl electrophiles with alkenylmetal nucleophiles—which probably proceeds via a radical pathway—can form and set quaternary stereocentres efficiently under mild conditions.

The use of protecting groups has been, and remains, instrumental in the development of organic synthesis. However, designing protecting-group-free strategies offers the challenge of developing useful new chemoselective processes as well as being inherently more step- and atom-economic. The constant pressure to prepare compounds in a more efficient manner has placed the process by which traditional synthetic chemistry is conducted under scrutiny. Areas that have the potential to be improved must be highlighted and modified, so that we can approach the criterion of the 'ideal synthesis'. One area that offers this prospect is the minimization of the use of protecting groups in synthesis. A protection/deprotection event introduces at least two steps into a sequence, incurring costs from additional reagents and waste disposal, and generally leads to a reduced overall yield. Here we present relevant historical context and highlight recent (post-2004) total syntheses that have developed new chemistry in an effort to exclude protecting groups. The invention of chemoselective methodologies is crucial to the execution of 'protecting-group-free' synthesis, and recent advances in this area are also highlighted.