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Synthesizing ring structure aviation fuels from biomass-derived platform molecules is challenging, especially for bridged ring structure aviation fuels which are typically achieved from fossil-derived chemicals. Herein, we report the synthesis of a series of ring structure biofuels in two steps by a combination of a solvent-free Michael-cyclization reaction and a hydrodeoxygenation (HDO) reaction from lignocellulose-derived 5,5-dimethyl-1,3-cyclohexanedione. These biofuels are obtained with high overall yields up to 90%, which exhibit high densities of 0.81 g cm−3-0.88 g cm−3 and high volumetric neat heat of combustion (VNHOC) values of 36.0 MJ L−1-38.6 MJ L−1. More importantly, bridged-ring structure hydrocarbons can also be achieved in two steps by a combination of a Robinson annulation reaction and an HDO reaction to afford the final products at high overall yields up to 90%. The bridged-ring structure products have comparable high densities and high VNHOC values to the best artificial fuel JP-10 (0.94 g cm−3 and 39.6 MJ L−1). The results demonstrate a promising way for the synthesis of high-density aviation fuels with different fuel properties at high yields.

ConspectusFrom the venerable Robinson annulation to the irreplaceable Diels-Alder cycloaddition, annulation reactions have fueled the progression of the field of natural product synthesis throughout the past century. In broader terms, the ability to form a cyclic molecule directly from two or more simpler fragments has transformed virtually every aspect of the chemical sciences from the synthesis of organic materials to bioconjugation chemistry and drug discovery. In this Account, we describe the evolution of our meroterpene synthetic program over the past five years, enabled largely by the development of a tailored anionic annulation process for the synthesis of hydroxylated 1,3-cyclohexanediones from lithium enolates and the reactive β-lactone-containing feedstock chemical diketene.First, we provide details on short total syntheses of the prototypical polycyclic polyprenylated acylphloroglucinol (PPAP) natural products hyperforin and garsubellin A, which possess complex bicyclo[3.3.1]nonane architectures. Notably, these molecules have served as compelling synthetic targets for several decades and induce a number of biological effects of relevance to neuroscience and medicine. By merging our diketene annulation process with a hypervalent iodine-mediated oxidative ring expansion, bicyclo[3.3.1]nonane architectures can be easily prepared from simple 5,6-fused bicyclic diketones in only two chemical operations. Leveraging these two key chemical reactions in combination with various other stereoselective transformations allowed for these biologically active targets to be prepared in racemic form in only 10 steps.Next, we extend this strategy to the synthesis of complex fungal-derived meroterpenes generated biosynthetically from the coupling of 3,5-dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate. A Ti(III)-mediated radical cyclization of a terminal epoxide was used to rapidly prepare a 6,6,5-fused tricyclic ketone which served as an input for our annulation/rearrangement process, ultimately enabling a total synthesis of protoaustinoid A, an important biosynthetic intermediate in DMOA-derived meroterpene synthesis, and its oxidation product berkeleyone A. Through a radical-based, abiotic rearrangement process, the bicyclo[3.3.1]nonane cores of these natural products could again be isomerized, resulting in the 6,5-fused ring systems of the andrastin family and ultimately delivering a total synthesis of andrastin D and preterrenoid. Notably, these isomerization transformations proved challenging when employing classic, acid-induced conditions for carbocation generation, thus highlighting the power of radical biomimicry in total synthesis. Finally, further oxidation and rearrangement allowed for access to terrenoid and the lactone-containing metabolite terretonin L.Overall, the merger of annulative diketene methodology with an oxidative rearrangement transformation has proven to be a broadly applicable strategy to synthesize bicyclo[3.3.1]nonane-containing natural products, a class of small molecules with over 1000 known members.

The first bioinspired and protecting group free total synthesis of the antibacterial sesquiterpenoid antroalbocin A has been achieved in five linear steps from a literature-known intermediate with an overall yield of 6.7%. An intramolecular Robinson annulation gave rapid access to the tricyclic enone as starting material for a photochemical domino process of deconjugation and sigmatropic 1,3 acyl shift. Herein we further describe studies towards the use of photolytic sigmatropic 1,3-acyl shifts in the synthesis of bridged terpenoid building blocks.

A convergent and efficient approach towards the total synthesis of Kadcotrione B is described. For this purpose, the syntheses of two fragments, 6/6/5-fused tricyclic ring and C-9 side chain, were accomplished. The salient features of these syntheses are the utilization of aldol condensation, Evans aldol reaction, Horner–Wadsworth–Emmons olefination, Michael addition, Robinson annulation, and Wacker oxidation.

(‒)-Morphine, which is selected as an essential medicine by World Health Organization, is widely applied in the treatment of the pain-related diseases. Due to its synthetically challenging molecular architecture and important clinical role, extensive synthetic studies of morphine-type alkaloids have been conducted. However, catalytic asymmetric total synthesis of (‒)-morphine remains a long-standing challenge. Here, we disclose an efficient enantioselective total synthesis of (‒)-morphine in a longest linear sequence of 16 steps. The key transformation features a highly enantioselective Robinson annulation enabled by our spiro-pyrrolidine catalyst to rapidly construct the densely functionalized cis-hydrodibenzofuran framework containing vicinal stereocenters with an all-carbon quaternary center. This asymmetric approach provides an alternative strategy for the synthesis of (‒)-morphine and its analogues., (‒)-Morphine is an essential medicine selected by the World Health Organization, however its catalytic asymmetric syntheses have been rarely reported. Here, the authors developed an intramolecular enantioselective Michael addition leading to (‒)-morphine in a longest linear sequence of 16 steps.

An efficient route for the synthesis of 5-acetylimidazoles and di/trisubstituted pyrimidines via iron-catalyzed cross-dehydrogenative coupling (CDC), with excellent tolerance and yields, has been developed. In this report, α,β-unsaturated aldehydes/ketones and N′-hydroxyl imidamides undergo [3+2] and [3+3] cycloadditions in two processes, involving iron-mediated Michael reaction, Robinson Annulation and 1,5-electrocyclization.

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (-)-daphenylline has been accomplished. The synthesis was started from (S)-carvone and proceeded via a stereoselective Mg(ClO4 )2 -catalyzed intramolecular amide addition cyclization, an intramolecular Diels-Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel-Crafts cyclization. The total synthesis of (-)-daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.

The expected (E)-but-3-en-2-ones compounds I and II (half curcuminoids) were obtained by the Claisen–Schmidt reaction between aldehydes 3,4-dimethoxybenzaldehyde or 4-nitrobenzaldehyde with acetone. Concomitantly, 3-methylcyclohex-2-enones compounds III and IV arose from an unexpected reaction of but-3-en-2-ones in the cascade reaction of a Michael-type addition of a second molecule of acetone followed by Robinson annulation under strong basic conditions. Both enones exhibit the (E)-configuration, compound I displays s-trans conformation, whereas compound II exhibits conformational disorder as solid solution of s-cis and s-trans conformations. The related 3-methylcyclohex-2-enones exhibit envelope conformation. Compound III constitutes an example of the rarest case of racemic solid solution (pseudoracemate), where a lack of chiral discrimination with respect to the two enantiomers leads to an enantiomeric disorder of a racemic mixture with different occupancies at the reference site. Due to the lack of strong hydrogen-bond donors in all compounds, the crystal packing is mainly stabilized by weak intermolecular C-H···O interactions between the molecules. The present work provides a new perspective on the search for by-products normally overlooked in Claisen–Schmidt condensations.

Lipases, a versatile class of biocatalysts, have been shown to function in non-aqueous media/organic solvents and to possess &ldquo, promiscuous&rdquo, catalytic activity for a wide range of organic transformations. In this study, we explored the biocatalytic properties of a library of commercially available lipases by screening them for catalysis of a one-pot synthesis of Wieland&ndash, Miescher ketone, an important intermediate in the synthesis of biologically active compounds such as steroids and terpenoids, from methyl vinyl ketone and 2-methyl-1,3-cyclohexanedione. As a direct outgrowth of this screen, we created an optimized procedure for Wieland&ndash, Miescher ketone (WMK) synthesis using crude lipase preparations, characterizing both reaction yield and enantiomeric excess. We also identified principal components of the crude lipase mixture through proteomics and present evidence for a non-lipolytic origin of the observed catalysis. Finally, using the optimized conditions developed in this study, we propose a general absorbance-based screening methodology for assessing biocatalytic potential of crude enzyme preparations for synthesis of WMK.

Lipases, a versatile class of biocatalysts, have been shown to function in non-aqueous media/organic solvents and to possess promiscuous catalytic activity for a wide range of organic transformations. In this study, we explore the biocatalytic properties of a library of commercially available lipases by screening them for catalysis of a one-pot synthesis of Wieland-Miescher Ketone, an important intermediate in the synthesis of biologically active compounds such as steroids and terpenoids, from methyl vinyl ketone and 2-methyl-1,3-cyclohexanedione. As a direct outgrowth of this screen, we have created an optimized procedure for Wieland-Miescher Ketone (WMK) synthesis using crude lipase preparations, characterizing both reaction yield and enantiomeric excess. We have also identified principal components of the crude lipase mixture through proteomics and present evidence for a non-lipolytic origin of the observed catalysis. Finally, using the optimized conditions developed in this study, we propose a general absorbance-based screening methodology for assessing biocatalytic potential of crude enzyme preparations for synthesis of WMK.

A chiral bifuntional thiourea catalyzed diastereo- and enantioselective Michael addition followed by an intramolecular Aldol reaction of 3-indolinone-2-carboxylates with cyclohexenone has been accomplished using a chiral thiourea catalyst. It is a novel strategy for the construction of chiral bridged tricyclic hydrocarbazole derivatives bearing four contiguous stereocenters with excellent diastereo- and enantioselectivity.

Robinson annulation may be useful for converting biomass-derived compounds into jet-fuel-ranged alkylcyclohexanes, but it has not been fully developed until now. Herein, a strategy for the synthesis of highly branched C15 alkylcyclohexanes with lignocellulose-derived furfural and 2,4-pentanedione was developed with Robinson annulation as the key step. Low-freezing-point (−81 °C) and high-density (0.8139 g/mL) highly branched alkylcyclohexanes were produced by two steps, namely, a one-pot cyclization process including the aldol condensation of furfural with 2,4-pentanedione and the subsequent Robinson annulation of the aldol adducts with 2,4-pentanedione over CoCl2·6H2O catalyst, then following with the Pd/NbOPO4-catalyzed hydrodeoxygenation.

The first total syntheses of five natural eremophilane-type sesquiterpenoids were achieved in 4-12 steps via a common synthetic intermediate. The syntheses feature a double Michael addition, Robinson annulation, α-enolization of an unsaturated ketone, and Pd-catalyzed Suzuki coupling reaction to install the side chain. This synthetic strategy could be easily extended to other eremophilane-type sesquiterpenoids with similar bicyclic skeletons.

Among the several variants of the highly useful and versatile Robinson annulation, a particular variation that involves ketones reacting with nonenolizable enones, while the α-carbons of the ketones act as nucleophiles at both steps of this cascade process, remains largely unexplored. Moreover, such a catalytic enantioselective reaction is exceptionally rare. While pursuing catalysis of this transformation, we developed two fluorogenic assays that, in combination with other analytic techniques, enabled rapid screening of several sets of catalysts. The first set of polymer-bound aminourea bifunctional organocatalysts was screened using a two-step fluorogenic protocol, designed for slower (e.g., heterogeneous) catalysts. Robinson annulation of acetone with 4′-nitrochalcone formed 3-(4-nitrophenyl)-5-phenyl-2-cyclohexenone, which, after a “developing” reductive treatment, was converted into the corresponding amino derivative, serving as a fluorescent reporter. On the other hand, a range of potentially faster homogeneous catalyst–cocatalyst systems were examined using a direct assay, where 4′-dimethylaminochalcone is converted into the corresponding cyclohexanone fluorescent reporter already upon annulation with acetone. In both cases, the combination of the fluorogenic protocols with high-performance liquid chromatography-based enantiomeric excess estimation enabled identification of lead catalysts, which promoted the enantioselective version of this variant of the annulation.

The Robinson annulation is a reaction that has been useful for numerous syntheses since its discovery in 1935, especially in the field of the steroid synthesis. The products are usually obtained after 3 consecutive steps which are the formation of an enolate (or derivative), a conjugate addition and an aldol reaction. Over the years, several methodological improvements were made for each individual step or alternative routes were devised to access the Robinson annulation products. The first part of this review outlines the most relevant developments towards the formation of Monocarbonyl-derived Robinson Annulation Products (MRA Products, MRAP) and Activated Monocarbonyl-derived Robinson Annulation Products (AMRA Products, AMRAP). The following chapters are then devoted to the diastereoselective and enantioselective access to these products while the last section describes the enantiomeric resolution of racemic mixtures.

The Robinson annulation is a reaction that has been useful for numerous syntheses since its discovery in 1935, especially in the field of steroid synthesis. The products are usually obtained after three consecutive steps: the formation of an enolate (or derivative), a conjugate addition, and an aldol reaction. Over the years, several methodological improvements have been made for each individual step or alternative routes have been devised to access the Robinson annulation products. The first part of this Review outlines the most relevant developments towards the formation of monocarbonyl-derived Robinson annulation products (MRA products, MRAPs) and activated monocarbonyl-derived Robinson annulation products (AMRA products, AMRAPs). The following sections are then devoted to the diastereoselective and enantioselective synthesis of these products, while the last section describes the enantiomeric resolution of racemic mixtures.

The widely occurring tetranortriterpene natural product gedunin has a well-established range of important biological properties. Although this molecule has received substantial semi-synthetic attention from medicinal chemists, it has not received devoted de novo synthetic attention since it was first isolated in 1960. A key feature of the approach presented herein was the decision to utilize a Robinson annulation reaction, which facilitated the installation of the challenging 7-acetoxy functional group and the completion of the fully functionalized ABC ring system.

The mechanism for the thiol mediated dehalogenation of α-halogenated carbonyls has remained an unresolved problem, despite its ongoing application in synthetic organic chemistry. Nakamura and co-workers first proposed that net dehalogenation occurs via sequential nucleophilic substitutions, while Israel and co-workers concluded that the rate at which dehalogenation occurred suggested that dehalogenation proceeds in a single concerted step. In this study, we investigated the debromination and nucleophilic substitution of 3-(bromoacetyl)coumarin with a variety of thiophenols, whose electron donating or withdrawing natures resulted in large variations in the degree of nucleophilic substitution and dehalogenation products, respectively. Results from these experiments, in addition to an unexpected formation of thioether containing dibenzo[ b , d ]pyran-6-ones from a Robinson annulation, has provided new evidence for this disputed mechanism.

The preparation through Robinson annulation of enantiopure building blocks with both academic and industrial relevance, such as the Wieland–Miescher and Hajos–Parrish ketones, has suffered from important drawbacks, such as the need for high catalyst loading or extremely long reaction times. Here we report a heterogenized organocatalyst based on Luo’s diamine for fast and broad-scope enantioselective Robinson annulation reactions. The polystyrene-supported diamine 19a enables the high-yield, highly enantioselective preparation of a wide range of chiral bicyclic enones under mild conditions, with reaction times as short as 60 min (batch) or residence times of 10 min (flow). In contrast with its homogeneous counterpart 19b, the catalytic resin 19a experiences a notable increase in catalytic activity with temperature in 2-MeTHF (a 10-fold decrease in reaction times without erosion in enantioselectivity is observed from room temperature to 55 °C). The scope of the transformation in batch mode has been illustrated with 14 examples, including examples only reported in poorly enantioenriched (22n) or in racemic form (22k). Enantiopure 22k has been used as the starting material for a straightforward formal synthesis of the antibiotic and antifeedant sesquiterpene (−)-isovelleral (24). The heterogenized catalyst 19a admits extended recycling (10 cycles) and has been used to develop the first asymmetric Robinson annulations in continuous flow. The potential of the flow process is illustrated by the large-scale preparation of the Wieland–Miescher ketone (65 mmol in 24 h of operation, TON of 117) and by a sequential flow experiment leading to a library of eight enantioenriched diketone compounds. &nbsp

Owing to their interesting biological activity and architectural complexity, Daphniphyllum alkaloids have triggered intensive research activities from the synthetic community. Nine types of Daphniphyllum alkaloids, such as daphniphylline-type, daphmanidin A-type, calyciphylline A-type, and yuzurimine-type alkaloids, have been accessed by total synthesis over past decades. However, more than twenty types of Daphniphyllum alkaloids remain inaccessible by chemical synthesis. Here, we wish to describe our recent efforts toward the total synthesis of daphniglaucin-C type alkaloids, namely, daphnimacropodines. Key features of our synthesis include a Robinson annulation and a Simmons-Smith cyclopropanation that constructed the pivotal vicinal quaternary centers, and a Horner-Wadsworth-Emmons reaction that forms the critical cyclopentene motif.

A new efficient method was developed for the synthesis of triaryl-substituted cyclohexenones and salicylates. The method is based on the Robinson annulation of readily available keto esters and chalcones, followed by the aromatization of the cyclohexenone moiety. The aromatization can be accomplished either by reaction with bromine in boiling chloroform or bromination with copper(II) bromide in ethanol followed by treatment with pyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The new synthetic method was also implemented in a one-pot protocol, which in some cases resulted in higher yields of the final product compared to those obtained in the stepwise synthesis.

We recently described the synthesis of an unusual tricyclic system, whereby a cis-decalin was fused to a cis-hydrindane. Herein, we wish to describe the elaboration of this system towards steroid-like frameworks. This report describes how, en route to an attempted cardiotonic steroid synthesis, we stereoselectively functionalized the leftmost cyclohexyl ring with an ester ready for steroidal A-ring formation. Ultimately however, the required transposition of the cyclohexylketone did not occur as expected and resulted in the subsequent Robinson annulation forming an unusual steroidal constitutional isomer – the saturated cyclopenta[c]phenanthrene. Remarkably, such unusual tetracyclic connectivity has been reported just once in 70 years.