Synthetic Studies of the Zoanthamine Alkaloids: Total Synthesis of Zoanthenol Based on an Isoaromatization Strategy

The total synthesis of zoanthenol, a unique aromatic member of the zoanthamine alkaloids, which has exhibited potent anti‐platelet activities on human platelet aggregation, is described in full detail. The key step involves a Brønsted acid‐promoted isoaromatization in the AB ring system to install the crucial aromatic ring. We have not only succeeded in the first total synthesis of zoanthenol, but also established an alternative efficient synthetic route from the commercially available norzoanthamine hydrochloride to zoanthenol.     

Construction of the benzylic quaternary carbon center of zoanthenol by intramolecular Mizoroki-Heck reaction of enone

[reaction: see text]. Stereocontrolled synthesis of the ABC ring framework of zoanthenol has been achieved. Our studies show that a beta,beta-disubstituted enone can act as a good acceptor of arylpalladium intermediates in the formation of a congested benzylic quaternary carbon center through an intramoleculer Mizoroki-Heck reaction. The cis B/C ring system was stereoselectively converted to the trans-fused framework through a SmI2-promoted deoxygenation of the alpha-hydroxy ketone.     

Total Synthesis of (−)‐Lundurine A and Determination of its Absolute Configuration

A 15‐step total synthesis of (?)‐lundurine A ( 1 ) from easily accessible (S)‐pyrrolidinone 18 is reported. A Simmons‐Smith reaction allows the efficient, simultaneous assembly of the cyclopropyl C ring, the six‐membered D ring, the seven‐membered E ring, and the quaternary carbon stereocenters at C2 and C7. The absolute configuration of natural (?)‐lundurine A was deduced to be 2R,7R,20R based on the stepwise construction of the stereocenters during the total synthesis.     

Catalytic diastereoselective construction of multiple contiguous quaternary carbon stereocenters via [2 + 2] cycloaddition and mechanistic insight

Multiple contiguous quaternary carbon stereocenters (CQS) are highly challenging, yet important structural motifs in organic synthesis. Here, we describe a visible light induced catalytic [2 + 2] cycloaddition approach that constructed up to four CQS in a pentacyclic fused ring system diastereoselectively, from the readily accessible dienamides with pendent heteroaryls. Variously substituted dienamides have been cyclized with heteroaryls to provide a range of novel CQS-containing scaffolds (26 examples, up to 96% yield and >20:1 dr ratio). Mechanistic studies revealed that it may proceed through an uncommon β-C radical initiated 7-endo cyclization from the biradical intermediate.     

Enantioselective total synthesis of macrolide antitumor agent (-)-lasonolide A

[structure: see text] An enantioselective total synthesis of (-)-lasonolide A is described. The upper tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3-dipolar cycloaddition reaction. The bicyclic isooxazoline led to the tetrahydropyran ring as well as the quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a catalytic asymmetric hetero-Diels-Alder reaction as the key step. Three stereocenters were enantioselectively installed in this single step reaction.     

Exploration of the enantioselective Birch-Cope sequence for the synthesis of carbocyclic quaternary stereocenters

Quaternary stereocenters on a 2-cyclohexen-1-one ring are synthesized with good to excellent levels of enantioselectivity. The quaternary stereocenter is created through a new synthetic sequence involving three reactions: the enantioselective Birch reduction-allylation, enol ether hydrolysis, and the Cope rearrangement. To illustrate the ability of the sequence to enantioselectively generate complex structures, a variety of substrates are described. Notably, the sequence works for the enantioselective generation of vicinal quaternary-tertiary stereocenters, the generation of congested arylic quaternary stereocenters, and hydroxyalkyl substituted quaternary stereocenters.     

The enantioselective Birch-Cope sequence for the synthesis of carbocyclic quaternary stereocenters. Application to the synthesis of (+)-mesembrine

A synthetic technique for generating carbocyclic quaternary stereocenters with exceptionally high levels of enantioselectivity is described. A sequence of three reactions, enantioselective Birch reduction-allylation, enol ether hydrolysis, and Cope rearrangement, is used to stereoselectively generate chiral quaternary centers on a 2-cyclohexen-1-one ring. The products of the sequence are 4,4-disubstituted-2-carboxamide-2-cyclohexen-1-one structures which are versatile intermediates in complex natural product synthesis. An application of the sequence to the synthesis of (+)-mesembrine illustrates the utility of these intermediates.     

Stereocontrol of All‐Carbon Quaternary Centers through Enantioselective Desymmetrization of Meso Primary Diols by Organocatalyzed Acyl Transfer

The symmetry breaking of meso primary diols bearing a tetrahydropyran ring was employed, using catalytic asymmetric acyl transfer, to control all‐carbon quaternary stereocenters. The planar chiral Fu DMAP catalyst was used in this reaction to reach a high degree of enantioselectivity (up to 97:3 e.r.) through a synergic effect combining a desymmetrization step and a kinetic resolution. Moreover, a beneficial effect was exhibited by C₆F₆ solvent, yielding the first example of an organocatalyzed asymmetric acyl transfer. The desymmetrized monoesters were then used to obtain, after a straightforward ring opening sequence, complex polyketide building blocks bearing all‐carbon quaternary stereocenters.     

Generation of all carbon quaternary stereocenters at the C-3 carbon of piperidinones and pyrrolidinones and its application in natural product total synthesis

Methodologies regarding the construction of an all carbon quaternary stereocenters at C-3 of lactams have posed significant challenges in the total synthesis of natural products. This review summarizes the advancements for the construction of an all carbon quaternary stereocenters at C-3 of piperidinones and pyrrolidinones and its application in the total synthesis of biologically active and architecturally complex alkaloids.     

Construction of Chiral Quaternary Carbon Centers via Asymmetric Metal Carbene gem-Dialkylation

The catalytic asymmetric construction of all-carbon quaternary stereocenters has received tremendous interest over the past decades, and numerous efficient protocols have been disclosed based on the formation of one C−C bond between two assembling reactants. However, the use of asymmetric multi-component reactions that build two C−C bonds on the same carbonic center with concomitant assembly of quaternary stereocenters is rare and remains challenging. Herein, we disclose an enantioselective three-component reaction of α-diazo ketones with alkenes and 1,3,5-triazines under dirhodium/chiral phosphoric acid cooperative catalysis, which leads to a practical and atom-economic synthesis of poly-functionalized chiral ketones that bear a α-quaternary stereocenter in generally good to high yields with excellent enantioselectivities. In comparison to the previous method for the construction of tertiary and quaternary stereocenters via carbene gem-difunctionalization reactions, this reaction features an unprecedented gem-dialkylation process via sequential installation of two C−C bonds on the carbene center in one reaction, providing an essential complement to the asymmetric construction of all-carbon quaternary stereocenters using common and readily available starting materials.     

Enantioselective Formation of Cyano‐Bearing All‐Carbon Quaternary Stereocenters: Desymmetrization by Copper‐Catalyzed N‐Arylation

The enantioselective construction of all‐carbon quaternary stereocenters is one of the most challenging fields in asymmetric synthesis. An asymmetric desymmetrization strategy offers an indirect and efficient method for the formation of all‐carbon stereocenters. An enantioselective formation of cyano‐bearing all‐carbon quaternary stereocenters in 1,2,3,4,‐tetrahydroquinolines and 2,3,4,5‐tetrahydro‐1H‐benzo[b]azepines by copper‐catalyzed desymmetric N‐arylation is demonstrated. The cyano group at the prochiral center plays a key role for the high enantioselectivity and works as an important functional group for further transformations. DFT studies provide a model which successfully accounts for the origin of enantioselectivity.     

A Stereoselective [3+1] Ring Expansion for the Synthesis of Highly Substituted Methylene Azetidines

The reaction of rhodium‐bound carbenes with strained bicyclic methylene aziridines results in a formal [3+1] ring expansion to yield highly substituted methylene azetidines with excellent regio‐ and stereoselectivity. The reaction appears to proceed through an ylide‐type mechanism, where the unique strain and structure of the methylene aziridine promotes a ring‐opening/ring‐closing cascade that efficiently transfers chirality from substrate to product. The resultant products can be elaborated into new azetidine scaffolds containing vicinal tertiary‐quaternary and even quaternary‐quaternary stereocenters.     

Catalytic Enantioselective Nazarov Cyclization: Construction of Vicinal All‐Carbon‐Atom Quaternary Stereocenters

The diastereoselective asymmetric synthesis of vicinal all‐carbon‐atom quaternary stereocenters is a challenging problem in organic synthesis for which only few solutions have been described. A catalytic asymmetric Nazarov cyclization of fully substituted dienones that provides cyclopentenone derivatives with vicinal quaternary stereocenters in high optical purity and as single diastereoisomers is now reported.     

Asymmetric synthesis of ABC tricyclic core in Daphniphyllum alkaloid 21-deoxy-macropodumine D

In this paper, we describe our efforts toward the asymmetric synthesis of Daphniphyllum alkaloid 21-deoxymacropodumine D which led to efficient preparation of a ABC tricyclic framework containing five consecutive stereocenters. This synthetic work features (1) utilization of an asymmetric conjugate addition to install the C5 all-carbon quaternary center, (2) an intramolecular aza-Michael addition followed by Pd-catalyzed α-alkenylation to build the bowl-shaped tricyclic core.     

Protecting-group-free total synthesis of 4-epi-phomonol

A concise first total synthesis of 4-epi-phomonol has been accomplished in 6 steps and 33% overall yield from (R)-1,2-epoxypentane. The key features of the synthesis include an application of protecting-group-free strategy, a prins cyclization to install the tetrahydropyran ring, and a substrate-controlled dihydroxylation to fix the stereocenters at the C3 and C4 positions.     

Construction of polycyclic structures with vicinal all-carbon quaternary stereocenters via an enantioselective photoenolization/Diels–Alder reaction

All-carbon quaternary stereocenters are ubiquitous in natural products and significant in drug molecules. However, construction of all-carbon stereocenters is a challenging project due to their congested chemical environment. And, when vicinal all-carbon quaternary stereocenters are present in one molecule, they will dramatically increase its synthetic challenge. A chiral titanium promoted enantioselective photoenolization/Diels–Alder (PEDA) reaction allows largely stereohindered tetra-substituted dienophiles to interact with highly active photoenolized hydroxy-o-quinodimethanes, delivering fused or spiro polycyclic rings bearing vicinal all-carbon quaternary centers in excellent enantiomeric excess through one-step operation. This newly developed enantioselective PEDA reaction will inspire other advances in asymmetric excited-state reactions, and could be used in the total synthesis of structurally related complex natural products or drug-like molecules for drug discovery.

An enantioselective PEDA reaction was developed to enable stereohindered dienophiles to interact with transient photoenolized hydroxy-o-quinodimethanes, delivering fused or spiro polycyclic rings bearing 2–3 vicinal all-carbon quaternary centers in good yield and excellent ee.     

Enantioselective synthesis of rumphellaone A via epoxy nitrile cyclization

The first enantioselective synthesis of rumphellaone A, a cytotoxic 4,5-seco-caryophyllane derivative incorporating a γ-lactone ring as its structural feature, has been achieved by using base-induced intramolecular cyclization of an epoxy nitrile intermediate to install its cyclobutane skeleton as well as three contiguous stereocenters as the key transformation.     

Trifluoroacetic anhydride promoted tandem conjugate addition of boronic acids/acetal ring opening

A new stereoselective tandem reaction consisting of the metal-free conjugate addition of boronic acids followed by an intramolecular ring opening of a cyclic acetal has been disclosed. Optically pure polysubstituted tetrahydropyrans have been synthesized diastereoselectively by this new reaction. Two new C-C bonds and up to three stereocenters are formed in a single step, allowing the generation of quaternary stereocenters.     

Highly enantioselective amination of alpha-substituted alpha-cyanoacetates with chiral catalysts accessible from both quinine and quinidine

[Reaction: see text] The catalytic construction of nitrogen-substituted quaternary stereocenters is an important and challenging task in asymmetric synthesis. In this paper, we describe the use of 6'-OH-modified cinchona alkaloids that are accessible from either quinine or quinidine for the development of a highly enantioselective amination of alpha,alpha-disubstituted carbonyl compounds that is suitable for the creation of nitrogen-substituted quaternary stereocenters in either the R or S configuration.     

Enantioselective Construction of Quaternary Stereocenters

The stereoselective formation of C-C bonds is of great importance for the synthesis of enantiomerically pure natural products and pharmaceuticals. A broad repertoire of chiral auxiliaries, reagents, and catalysts can be utilized for the reliable generation of tertiary stereocenters. In contrast, the synthesis of organic compounds with quaternary stereocenters is a much more demanding and challenging task. Every enantioselective synthetic method can demonstrate its value through the generation of a fully substituted carbon center. In this Minireview examples of newer stoichiometric and catalytic methods are summarized which have proved their suitability for the enantioselective construction of quaternary stereocenters.