An asymmetric synthesis of (−)-callyspongiolide is described. The route builds the macrolide domain atypically from a disaccharide and a monoterpene without passing through a seco-acid. Chiral iridium catalysis selectively joins fragments. Subsequent degradation of an imbedded butyrolactone via perhemiketal fragmentation affords a stereo-and regio-defined homoallylic alcohol that is engaged directly in a carbonylative macrolactonization. Further elaboration of the polyunsaturated appendage provides the natural product in a particularly direct and flexible manner.

In the presence of a novel, tert-butyl-substituted squaramide-based catalyst, enolizable anhydrides react with alkylidene oxindoles to generate spirooxindole products of significant synthetic interest with excellent enantio- and diastereocontrol. The methodology is of wide scope and encompasses both homophthalic and glutaconic anhydride derivatives, which lead to structurally diverse products. Glutaconic acid-derived anhydrides undergo a clean post-cyclization decarboxylation process which is not a feature of reactions involving homophthalic acid-derived anhydrides. The unusual influence of reaction temperature on diastereocontrol has been probed, with reactions occurring at 30 °C and -30 °C delivering products epimeric at one stereocenter only, in near optical purity.

In the presence of a highly efficient novel bifunctional organocatalyst at low loadings under mild conditions, enolizable homophthalic anhydrides can be added to a range of aromatic and aliphatic aldehydes to give dihydroisocoumarins, with excellent yields and diastereo- and enantiocontrol (up to 99% ee).

This review examines the state of the art in synthesis as it relates to the building of complex architectures on scales sufficient to drive human drug trials. We focus on the relatively few instances in which a natural-product-based development candidate has been manufactured de novo, rather than semisynthetically. This summary provides a view of the strengths and weaknesses of current technologies, provides perspective on what one might consider a practical contribution, and hints at directions the field might take in the future.

The Tishchenko reaction [1] (discovered by Claisen [2] in 1887) is the disproportionation of two aldehyde molecules to furnish an ester product (Scheme 1).[3] Aluminum alkoxides [1,4] and boric acid, [5] were the first classes of synthetically relevant homogeneous catalysts [6] for this reaction, these were then followed by a range of transition-metal complexes of low to high catalytic activity but often limited practical utility. [7,8] More recently, lanthanide, [9] actinide, [10] and calcium [11] complexes capable of promoting aldehyde dimerization with excellent activity have been reported. A generalized mechanistic outline of the process is given in Scheme 1: reaction of the transition-metal complex 1 with the aldehyde generates the metal alkoxide 2, which acts as the hydride-transfer agent in a metal-mediated redox process (i.e. 3) leading to ester 4.[12]The Tishchenko reaction is an unusual process from a mechanistic standpoint with the potential to allow chemists to plan the synthesis of ester products through an unconventional disconnection. While recent advances in catalyst development have resulted in increased promise as a general synthetic methodology, the utility of the Tishchenko reaction is somewhat limited by two factors: a) Often the reported catalyst systems result in lower yields of isolated products from substituted benzaldehydes, and b) intermolecular crossed-Tishchenko reactions between equimolar amounts of two different carbonyl moieties are generally not possible. In particular no examples of intermolecular cross-coupling [13,14] between an aldehyde and a ketone are known, meaning that the intermolecular reaction cannot currently be utilized to generate new stereogenic centers. We were therefore encouraged to attempt the development of an alternative catalyst system for the intermolecular Tishchenko process. Our objective was to devise a simple, inexpensive, and easy to use small-molecule promoter, the steric and electronic characteristics of which could be readily tuned, with the eventual goal of broadening the scope of the Tishchenko reaction to include ketone substrates. We were inspired by the mode of action of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (G3PDHase), which promotes aldehyde oxidation through base-catalyzed addition of a cysteine residue to the aldehyde substrate to give the corresponding hemithioacetal conjugate base 5 (Scheme 2, A), which participates in an intermolecular hydride-transfer reaction with enzyme-bound NAD + . The resulting electrophilic thioester 6 then undergoes either hydrolysis or substitution by inorganic phosphate (depending on the enzyme variant). [15][16][17] We postulated the viability of an artificial process in which an analogous hemithioacetal anion 9 generated from benzaldehyde (8) and a bromomagnesium thiolate [18] could transfer hydride [19,20] to another carbonyl moiety to give magnesium alkoxide 10 and thioester 11, [21] which would subsequently couple to form the ester product 12 with regeneration of the thiolate catal...

A new, highly enantio- and diastereoselective catalytic asymmetric formal cycloaddition of aryl succinic anhydrides and aldehydes which generates paraconic acid (γ-butyrolactone) derivatives is reported.

The first catalytic, asymmetric reactions of imines with homophthalic anhydride to form disubstituted 3,4-dihydroisoquinolones are reported. The use of N-mesyl aldimines is key, as more basic imines undergo rapid uncatalysed reactions, while imines possessing larger N-sulphonyl substituents form lactams with lower ee.

The first examples of asymmetric Tamura cycloaddition reactions involving singly activated alkenes are reported. Homophthalic anhydride reacts with α-methyl nitrosytrenes in the presence of an alkaloid-based catalyst to generate fused bicyclic aromatic ketone products with three new stereocentres (which are susceptible to subsequent equilibration) in 12-99% ee. An unusual equilibration process which occurs in methanolic medium in the absence of a recognisable base via proton transfer at the α-carbon of an ester was investigated experimentally and computationally.