Editing Tetrasubstituted Carbon: Dual C-O Bond Functionalization of Tertiary Alcohols Enabled by Palladium-Based Dyotropic Rearrangement.

Many elegant asymmetric syntheses of enantioenriched tertiary alcohols have been developed, and both the transition metal-catalyzed and the radical-based peripheral functionalization of tertiary alcohols have attracted intensive research interest in recent years. However, directly editing tetrasubstituted carbons remains challenging. Herein, we report a Pd-catalyzed migratory fluoroarylation reaction that converts tertiary alcohols to α-fluorinated tertiary alkyl ethers in good to excellent yields. An unprecedented 1,2-aryl/PdIV dyotropic rearrangement along the C-O bond, integrated in a PdII-catalyzed domino process, is key to the dual functionalization of both the hydroxyl group and the tetrasubstituted carbon. This reaction, which is compatible with a broad range of functional groups, generates a tertiary alkyl fluoride and an alkyl-aryl ether functional group with inversion of the absolute configuration at the tetrasubstituted stereocenter.

Asymmetric Total Synthesis of Cephalotaxus Diterpenoids: Cephinoid P, Cephafortoid A, 14-epi-Cephafortoid A and Fortalpinoids M-N, P.

The asymmetric total syntheses of cephalotaxus C19 diterpenoids, bearing a unique cycloheptene A ring with a chiral methyl group at C-12, were disclosed based on a universal strategy. Six members, including cephinoid P, cephafortoid A, 14-epi-cephafortoid A and fortalpinoids M-N, P, were accomplished for the first time. The concise approach relies on two crucial steps: (1) a Nicholas/Hosomi-Sakurai cascade reaction was developed to efficiently generate the cycloheptene ring bearing a chiral methyl group; (2) an intramolecular Pauson-Khand reaction was followed to facilitate the construction of the complete skeleton of target molecules. Our studies provide a new strategy for the synthetic analysis of cephalotaxus diterpenoids and structurally related polycyclic natural products.

Enantioselective Total Synthesis of (+)-Stephadiamine.

An asymmetric synthesis of (+)-stephadiamine has been accomplished featuring (a) an enantioselective dearomatizative Michael addition to generate a quaternary stereocenter; (b) a domino sequence involving reductive generation of nitrone from γ-nitro ketone followed by a highly regio- and diastereo-selective intramolecular [3 + 2] cycloaddition to construct the aza[4,3,3]propellane core with concurrent generation of two quaternary stereocenters and two functional groups ready for subsequent transformations; (c) the Curtius rearrangement of the sensitive α,α-disubstituted malonic acid mono ester for the installation of α,α-disubstituted amino ester moiety; (d) a benzylic C-H oxidation under photoredox catalytic conditions; and (e) a highly diastereoselective ketone reduction affording δ-hydroxyester preorganized for lactonization.

Asymmetric Total Synthesis of Hasubanan Alkaloids: Periglaucines A-C, N,O-Dimethyloxostephine and Oxostephabenine.

We report herein the asymmetric total synthesis of periglaucines A-C, N,O-dimethyloxostephine and oxostephabenine. The key strategies used include: 1) a RhI -catalyzed regio- and diastereoselective Hayashi-Miyaura reaction to connect two necessary fragments; 2) an intramolecular photoenolization/Diels-Alder (PEDA) reaction to construct the highly functionalized tricyclic core skeleton bearing a quaternary center; 3) a bio-inspired intramolecular Michael addition and transannular acetalization to generate the aza[4.4.3]propellane and the tetrahydrofuran ring.

Exo-Selective and Enantioselective Photoenolization/Diels-Alder Reaction.

An unusual exo-selective photoenolization/Diels-Alder reaction of electron-rich 2-methylbenzaldehydes and dienophiles containing a benzoyl group at its α position was reported herein. The chiral TADDOL-type ligand plays a key role in this process: (1) accelerating the reaction; (2) controlling the enantioselectivity; and (3) improving and tuning the diastereoselectivity of the reaction.

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.

Asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B.

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6-7 steps using an easily accessible meso-cyclohexadienone derivative. The [6,6]-bicyclic decalin B-C ring and the all-carbon quaternary stereocenter at C-6 were prepared via a desymmetric intramolecular Michael reaction with up to 97% ee. The naphthalene diol D-E ring was constructed through a sequence of Ti(Oi-Pr)4-promoted photoenolization/Diels-Alder, dehydration, and aromatization reactions. This asymmetric strategy provides a scalable route to prepare target molecules and their derivatives for further biological studies.

Asymmetric Total Synthesis and Biosynthetic Implications of Perovskones, Hydrangenone, and Hydrangenone B.

Perovskones and hydrangenones are a family of structurally complex triterpenoids that were mainly isolated from the genus Salvia medicinal plants. These isoprenoids exhibit a broad range of biological activities, such as antitumor and antiplasmodial activities. Here, we report the collective total synthesis of perovskone, perovskones C, D, F, hydrangenone, and hydrangenone B. The key strategies in this work include the following: (1) an asymmetric photoenolization/Diels-Alder reaction was developed to construct a tricyclic ring bearing three contiguous quaternary centers, which was used to build the core icetexane skeleton; (2) a bioinspired Diels-Alder reaction of perovskatone D with trans-α-ocimene was applied to stereospecifically generate perovskones; (3) late-stage oxidations and ring forming steps were developed to synthesize perovskones and hydrangenones. Our synthetic work suggests that (1) perovskatone D may serve as the precursor of the biosynthesis of perovskones and (2) the formation of hydrangenone and hydrangenone B, containing a five-membered D ring, may involve an oxidative ring cleavage and ring regeneration process.

Recent advances in the application of Diels-Alder reactions involving o-quinodimethanes, aza-o-quinone methides and o-quinone methides in natural product total synthesis.

In recent decades, transient and highly reactive ortho-quinodimethanes (o-QDMs), ortho-quinone methides (o-QMs) and aza-ortho-quinone methides (aza-o-QMs) have attracted much attention and have been extensively studied and applied in organic synthesis, especially natural product total synthesis. This review summarizes recent advances in Diels-Alder reactions involving in situ-generated o-QDMs, o-QMs and aza-o-QMs, highlighting the power and potential of this strategy in organic synthesis and natural product total synthesis. An overview of the methods for generating these intermediates is also available.

Ti(Oi-Pr)4-promoted photoenolization Diels-Alder reaction to construct polycyclic rings and its synthetic applications.

Stereoselective construction of polycyclic rings with all-carbon quaternary centers, and vicinal all-carbon quaternary stereocenters, remains a significant challenge in organic synthesis. These structures can be found in a wide range of polycyclic natural products and drug molecules. Here we report a Ti(Oi-Pr)4-promoted photoenolization/Diels-Alder (PEDA) reaction to construct hydroanthracenol and related polycyclic rings bearing all-carbon quaternary centers. This photolysis proceeds under mild conditions and generates a variety of photo-cycloaddition products in good reaction efficiency and stereoselectivity (48 examples), and has been successfully used in the construction of core skeleton of oncocalyxones, tetracycline and pleurotin. It also provides a reliable method for the late-stage modification of natural products bearing enone groups, such as steroids. The total synthesis of oncocalyxone B was successfully achieved using this PEDA approach.Anthracenols with multiple chiral centres are common motifs in natural products. Here, the authors show a highly stereoselective photoenolization/Diels-Alder methodology involving a key Lewis acid reagent enabling the efficient construction of a family of anthracenol derivatives with quaternary centers.

Total synthesis of gracilamine.

The total synthesis of gracilamine, a pentacyclic Amaryllidaceae alkaloid, was achieved from simple building blocks. The synthesis features a mild photo-Nazarov reaction, intramolecular 1,4-addition, and an intramolecular Mannich reaction. This approach not only confirms the C6 stereochemistry of natural gracilamine, and also provides a novel solution to prepare its derivatives and structurally related natural products.

A photo-induced C-O bond formation methodology to construct tetrahydroxanthones.

A metal-free, photo-induced C-O bond formation methodology was developed to construct tetrahydroxanthones. This mild and efficient methodology was based on intramolecular oxygen trapping of the reactive species produced by photolytic activation of a C-Cl bond. We believe this method could be used in the synthesis of related xanthone-type natural products.