Total Synthesis and Prediction of Ulodione Natural Products Guided by DFT Calculations.

A biomimetic synthetic strategy has resulted in a two-step total synthesis of (±)-ulodione A and the prediction of two potential natural products, (±)-ulodiones C and D. This work was guided by computational investigations into the selectivity of a proposed biosynthetic Diels-Alder dimerization, which was then utilized in the chemical synthesis. This work highlights how biosynthetic considerations can both guide the design of efficient synthetic strategies and lead to the anticipation of new natural products.

Total synthesis of incargranine A.

Synthetic studies into the origins of the alkaloid incargranine A have resulted in the development of a four-step (longest linear sequence) total synthesis. This synthesis has been scaled-up to provide gram-scale quantities of material, which would alternatively require extraction of several metric-tons of dried-whole Chinese Trumpet-Creeper plants (Incarvillea mairei var. grandiflora).

High Activity and Efficient Turnover by a Simple, Self-Assembled "Artificial Diels-Alderase".

The Diels-Alder (DA) reaction is a cornerstone of synthesis, yet Nature does not use catalysts for intermolecular [4+2] cycloadditions. Attempts to create artificial "Diels-Alderases" have also met with limited success, plagued by product inhibition. Using a simple Pd2L4 capsule we now show DA catalysis that combines efficient turnover alongside enzyme-like hallmarks. This includes excellent activity (kcat/kuncat > 103), selective transition-state stabilization comparable to the most proficient DA catalytic antibodies, and control over regio- and chemoselectivity that would otherwise be difficult to achieve using small-molecule catalysts. Unlike other catalytic approaches that use synthetic capsules, this method is not defined by entropic effects; instead multiple H-bonding interactions modulate reactivity, reminiscent of enzymatic action.

Bio-inspired Domino oxa-Michael/Diels-Alder/oxa-Michael Dimerization of para-Quinols.

A bio-inspired, pyrrolidine-mediated, dimerization of para-quinols has been developed. It represents one of the most complex, yet general, dimerization reactions ever disclosed, selectively forming four new bonds, four new rings, and eight new contiguous stereogenic centres. The para-quinol starting materials are easily handled, bench-stable compounds, accessed in just one step from aromatic feedstocks. The reaction can be scaled up to give grams of polycyclic material, primed for further elaboration.

The importance of asking "how and why?" in natural product structure elucidation.

Covering: up to 2017This review highlights why careful consideration of the biosynthetic origin (the how) and the biological function (the why) of a natural product can be so useful during the determination of its structure. Recent examples of structural reassignments inspired by biosynthetic and functional insights will be presented. This review will demonstrate the importance of viewing the origin, structure and function of a natural product as intertwined threads of a single story, best viewed as a whole rather than as discrete topics.

Total Synthesis of a Dimeric Thymol Derivative Isolated from Arnica sachalinensis.

The total synthesis of a dimeric thymol derivative (thymarnicol) isolated from Arnica sachalinensis was accomplished in 6 steps. A key biomimetic Diels-Alder dimerization was found to occur at ambient temperature and the final oxidative cyclization occurs when the substrate is exposed to air and visible light. These results indicate that this natural product is likely the result of spontaneous (non-enzyme-mediated) reactivity.

Total Synthesis of Millingtonine.

Millingtonine is a glycosidic alkaloid that exists as a pair of pseudo-enantiomeric diastereomers. Consideration of the likely biosynthetic origins of this unusual natural product has resulted in the development of a seven-step total synthesis. Results from this synthetic work provide evidence in support of a proposed network of biosynthetic pathways that can account for the formation of several phenylethanoid natural products.

Total synthesis of ramonanins†A-D.

The first total synthesis of the ramonanin family of lignan natural products is described. The short synthesis involves a 2,5-diaryl-3,4-dimethylene tetrahydrofuran intermediate, which participates in an unexpectedly facile Diels-Alder dimerization, generating all four natural products. Insights into the reactivity and stereoselectivity of the key dimerization are provided through computational studies employing B3LYP/6-31G(d) and M06-2X/6-31G(d) model chemistries.

Stereoretentive enantioconvergent reactions.

Enantioconvergent reactions are pre-eminent in contemporary asymmetric synthesis as they convert both enantiomers of a racemic starting material into a single enantioenriched product, thus avoiding the maximum 50% yield associated with resolutions. All currently known enantioconvergent processes necessitate the loss or partial loss of the racemic substrate's stereochemical information, thus limiting the potential substrate scope to molecules that contain labile stereogenic units. Here we present an alternative approach to enantioconvergent reactions that can proceed with full retention of the racemic substrate's configuration. This uniquely stereo-economic approach is possible if the two enantiomers of a racemic starting material are joined together to form one enantiomer of a non-meso product. Experimental validation of this concept is presented using two distinct strategies: (1) a direct asymmetric coupling approach, and (2) a multicomponent approach, which exhibits statistical amplification of enantiopurity. Thus, the established dogma that enantioconvergent reactions require substrates that contain labile stereogenic units is shown to be incorrect.

A bioinspired, one-step total synthesis of peshawaraquinone.

A concise synthesis of a stereochemically complex meroterpenoid, peshawaraquinone, via the unsymmetrical dimerization of its achiral precursor, dehydro-α-lapachone, is reported. Enabled by reversible oxa-6π-electrocyclizations of 2H-pyran intermediates, the base-catalyzed dimerization sets up an intramolecular (3 + 2) cycloaddition, with the formation of six stereocenters during the cascade. Combining the generation and in situ dimerization of dehydro-α-lapachone allows a one-step total synthesis of peshawaraquinone from lawsone and prenal.

Natural product anticipation through synthesis.

Natural product synthesis remains one of the most vibrant and intellectually rewarding areas of chemistry, although the justifications for pursuing it have evolved over time. In the early years, the emphasis lay on structure elucidation and confirmation through synthesis, as exemplified by celebrated studies on cocaine, morphine, strychnine and chlorophyll. This was followed by a phase where the sheer demonstration that highly complex molecules could be recreated in the laboratory in a rational manner was enough to justify the economic expense and intellectual agonies of a synthesis. Since then, syntheses of natural products have served as platforms for the demonstration of elegant strategies, for inventing new methodology 'on the fly' or to demonstrate the usefulness and scope of methods established with simpler molecules. We now add another aspect that we find fascinating, viz. 'natural product anticipation'. In this Review, we survey cases where the synthesis of a compound in the laboratory has preceded its isolation from nature. The focus of our Review lies on examples where this anticipation of a natural product has triggered a successful search or where synthesis and isolation have occurred independently. Finally, we highlight cases where a potential natural product structure has been suggested as a result of synthetic endeavours but not yet confirmed by isolation, inviting further collaborations between synthetic and natural product chemists.

Unified total synthesis of the brevianamide alkaloids enabled by chemical investigations into their biosynthesis.

The bicyclo[2.2.2]diazaoctane alkaloids are a vast group of natural products which have been the focus of attention from the scientific community for several decades. This interest stems from their broad range of biological activities, their diverse biosynthetic origins, and their topologically complex structures, which combined make them enticing targets for chemical synthesis. In this article, full details of our synthetic studies into the chemical feasibility of a proposed network of biosynthetic pathways towards the brevianamide family of bicyclo[2.2.2]diazaoctane alkaloids are disclosed. Insights into issues of reactivity and selectivity in the biosynthesis of these structures have aided the development of a unified biomimetic synthetic strategy, which has resulted in the total synthesis of all known bicyclo[2.2.2]diazaoctane brevianamides and the anticipation of an as-yet-undiscovered congener.

Enantioselective para-Claisen Rearrangement for the Synthesis of Illicium-Derived Prenylated Phenylpropanoids.

The development of the first enantioselective para-Claisen rearrangement has been achieved. Using a chiral aluminum Lewis acid, illicinole is rearranged to give (-)-illicinone A (er 87:13), which can then be converted into more complex Illicium-derived prenylated phenylpropanoids. The absolute configurations of the natural products (+)-cycloillicinone and (-)-illicarborene A have been determined, and our results cast doubt on the enantiopurity of the natural samples.

Total synthesis of brevianamide A.

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.

Total Synthesis of (-)-Angiopterlactone B.

An enantioselective total synthesis of (-)-angiopterlactone B has been accomplished in four steps. The synthesis features a proposed biomimetic domino ring-contraction/oxa-Michael/Michael dimerization sequence, forming three new bonds, two new rings, and three new contiguous stereogenic centers in a single step. It has been determined that the originally proposed absolute configuration of natural (+)-angiopterlactone B needs revision. This reveals that angiopteroside, a known glycoside natural product, is the likely biosynthetic precursor to (+)-angiopterlactone B.