Enantioselective Total Synthesis of (+)‐Neostenine

A chirality transfer approach using acyclic polyol intermediates for the synthesis of (+)‐neostenine ( 1 ) has been developed. The sequential Overman/Claisen rearrangement of an allylic 1,2‐diol was especially useful, installing two contiguous stereocenters with complete diastereoselectivity in a one‐pot sequence. The SmI₂‐mediated cyclization and the subsequent chemoselective reduction of a lactam moiety accomplished the first enantioselective total synthesis of (+)‐neostenine ( 1 ).     

Highly Enantioselective Synthesis of Propargyl Amide with Vicinal Stereocenters through Ir‐Catalyzed Hydroalkynylation

Chiral propargyl amines are valuable synthetic intermediates for the preparation of biologically active compounds and functionalized amines. Catalytic methods to access propargyl amines containing vicinal stereocenters with high diastereoselectivity are particularly rare. We report an unprecedented strategy for the synthesis of enantioenriched propargyl amines with two stereogenic centres. An iridium complex, ligated by a phosphoramidite ligand, catalyzes the hydroalkynylation of β,β‐disubstituted enamides to afford propargyl amides in a highly regio‐, diastereo‐, and enantioselective fashion. Stereodivergent synthesis of all four possible stereoisomers was achieved using this strategy.     

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.     

Concise and Enantioselective Total Synthesis of (−)‐Mehranine, (−)‐Methylenebismehranine,and Related Aspidosperma Alkaloids

We report an efficient and highly stereoselective strategy for the synthesis of Aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent diastereoselectivity due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the Aspidosperma alkaloids (?)‐mehranine and (+)‐(6S,7S)‐dihydroxy‐N‐methylaspidospermidine. A late‐stage dimerization of (?)‐mehranine mediated by scandium trifluoromethanesulfonate completed the first total synthesis of (?)‐methylenebismehranine.     

Enantioselective Total Synthesis of (+)‐Steenkrotin A and Determination of Its Absolute Configuration

The first enantioselective total synthesis of (+)‐steenkrotin A has been achieved in 18 steps and 4.2 % overall yield. The key features of the strategy entail a Rh‐catalyzed O?H bond insertion followed by an intramolecular carbonyl‐ene reaction, two sequential SmI₂‐mediated Ueno–Stork and ketyl–olefin cyclizations, and a cascade intramolecular aldol condensation/vinylogous retro‐aldol/aldol process with inversion of the relative configuration at the C7 position. The absolute configuration of (+)‐steenkrotin A was determined based on the stepwise construction of the stereocenters during the total synthesis.     

Enantioselective Total Synthesis of (−)‐Terengganensine A

A seven‐step enantioselective total synthesis of (?)‐terengganensine A, a complex heptacyclic monoterpene indole alkaloid, was accomplished. Key steps included: a) Noyori's catalytic enantioselective transfer hydrogenation of the iminium salt to set up the absolute configuration at the C21 position; b) a highly diastereoselective C7 benzoyloxylation with dibenzoyl peroxide under mild conditions; and c) an integrated one‐pot oxidative cleavage of cyclopentene/triple cyclization/hydrolysis sequence for the construction of the dioxa azaadamantane motif with complete control of four newly generated stereocenters.     

Enantioselective Total Synthesis of (+)‐Flavisiamine F via Late‐Stage Visible‐Light‐Induced Photochemical Cyclization

The structural features Kopsia alkaloids, in particular multiple all‐carbon quaternary stereocenters in a caged and strained polycyclic skeleton, poses particular challenges for enantioselective total synthesis. Herein, we reported the first total synthesis of (+)‐flavisiamine F. The synthetic approach involved a room‐temperature Overman rearrangement for introducing the chiral amine at C21, a TMS‐promoted ketal Claisen rearrangement for constructing the all‐carbon quaternary stereocenter at C20, and a late‐stage visible‐light‐induced photochemical cyclization for establishing the all‐carbon quaternary stereocenter at C7.     

Palladium‐Titanium Relay Catalysis Enables Switch from Alkoxide‐π‐Allyl to Dienolate Reactivity for Spiro‐Heterocycle Synthesis

Reported herein is the divergent syntheses of [5,5] and [6,5] spiro‐heterocycles under Lewis‐acid‐assisted palladium catalysis. In particular, an unprecedented switch from alkoxide‐π‐allyl to dienolate reactivity was achieved by the use of palladium‐titanium relay catalysis, and represents umpolung reactivity of vinylethylene carbonates. This method uses a simple procedure and commercially available catalysts, and delivers both classes of spiro‐heterocycles, bearing three contiguous stereocenters, in high yield and uniformly excellent diastereoselectivity.     

Stereocontrol by Quaternary Centres: A Stereoselective Synthesis of (−)‐Luminacin D

Very high diastereoselectivity can be achieved by 1,3‐chelation‐controlled allylation of aldehydes that possess a non‐chelating α‐ether substituent, even if the α‐position is a quaternary centre and/or a spiro‐epoxide. This reaction was used as a key step in an enantioselective synthesis of the angiogenesis inhibitor luminacin D.     

Biomimetic Total Synthesis of Hyperjapones A–E and Hyperjaponols A and C

Hyperjapones A–E and hyperjaponols A–C are complex natural products of mixed aromatic polyketide and terpene biosynthetic origin that have recently been isolated from Hypericum japonicum. We have synthesized hyperjapones A–E using a biomimetic, oxidative hetero‐Diels–Alder reaction to couple together dearomatized acylphloroglucinol and cyclic terpene natural products. Hyperjapone A is proposed to be the biosynthetic precursor of hyperjaponol C through a sequence of: 1) epoxidation; 2) acid‐catalyzed epoxide ring‐opening; and 3) a concerted, asynchronous alkene cyclization and 1,2‐alkyl shift of a tertiary carbocation. Chemical mimicry of this proposed biosynthetic sequence allowed a concise total synthesis of hyperjaponol C to be completed in which six carbon–carbon bonds, six stereocenters, and three rings were constructed in just four steps.     

Diversity‐oriented Construction of Chromanone‐fused Polycyclic Pyrrolidinyl‐dispirooxindoles

Achieved herein is a novel diversity‐oriented one‐pot multicomponent synthesis of polycyclic pyrrolidinyl‐dispirooxindoles 3 . The key pyrrolidine forming reaction is the 1,3‐dipolar cycloaddition event of isatylidenyl‐chromanones 2 with azomethine ylides (thermally generated in situ from isatins and proline or thioproline). Products bearing four consecutive stereocenters consist of two oxindole moieties and a pyrrolidinyl core, including vicinal spiroquaternary stereocenters fused in one ring structure, were smoothly obtained in high yields (up to 89% yield) with good diastereoselectivity (up to >20:1). Valuable feature of this method was the design of new hybrid architectures for biological screenings through creating molecular diversity and complexity by means of the generation of several bonds and rings in a single operation. In particular, their biological activity against human leukemia cells K562 and normal L929 cells have been evaluated. These results suggested changes of this chromanone group could obviously impact the activity, and a chromanone group located in the polycyclic pyrrolidinyl‐dispirooxindoles is beneficial for the activity. What is more, the results also indicated that chromanone‐fused polycyclic pyrrolidinyl‐dispirooxindoles 3 have selective cytotoxicity against cancer cells K562 compared with normal cells L929.     

Total Synthesis of Potent Antitumor Agent (−)‐Lasonolide A: A Cycloaddition‐Based Strategy

A detailed account of the enantioselective total synthesis of (?)‐lasonolide A is described. Our initial synthetic route to the top tetrahydropyran ring involved Evans asymmetric alkylation as the key step. Initially, we relied on the diastereoselective alkylation of an α‐alkoxyacetimide derivative containing an α′ stereogenic center and investigated such an asymmetric alkylation reaction. Although alkylation proceeded in good yield, the lack of diastereoselectivity prompted us to explore alternative routes. Our subsequent successful synthetic strategies involved highly diastereoselective cycloaddition routes to both tetrahydropyran rings of lasonolide A. The top tetrahydropyran ring was constructed stereoselectively by an intramolecular 1,3‐dipolar cycloaddition reaction. The overall process constructed a bicyclic isoxazoline, which was later unravelled to a functionalized tetrahydropyran ring as well as a quaternary stereocenter present in the molecule. The lower tetrahydropyran ring was assembled by a Jacobsen catalytic asymmetric hetero‐Diels–Alder reaction as the key step. The synthesis also features a Lewis acid catalyzed epoxide opening to form a substituted ether stereoselectively.     

Total Synthesis of (+)‐Neomarinone

The first total synthesis of (+)‐neomarinone has been achieved by following a concise and convergent route using methyl (R)‐lactate and (R)‐3‐methylcyclohexanone as chiral building blocks. Key steps of the synthesis are the stereocontrolled formation of the two quaternary stereocenters by diastereoselective 1,4‐conjugate addition and enolate alkylation reactions, and the construction of the furanonaphthoquinone skeleton by regioselective Diels–Alder reaction between a 1,3‐bis(trimethylsilyloxy)‐1,3‐diene and a bromoquinone. The synthesis proves the relative and absolute stereochemistry of natural neomarinone.     

Synthesis of (±)‐Tetrapetalone A‐Me Aglycon

The first synthesis of (±)‐tetrapetalone A‐Me aglycon is described. Key bond‐forming reactions include Nazarov cyclization, a ring‐closing metathesis promoted with complete diastereoselectivity by a chiral molybdenum‐based complex, tandem conjugate reduction/intramolecular aldol cyclization, and oxidative dearomatization.     

Cascade Synthesis of Five‐Membered Lactones using Biomass‐Derived Sugars as Carbon Nucleophiles

We report the cascade synthesis of five‐membered lactones from a biomass‐derived triose sugar, 1,3‐dihydroxyacetone, and various aldehydes. This achievement provides a new synthetic strategy to generate a wide range of valuable compounds from a single biomass‐derived sugar. Among several examined Lewis acid catalysts, homogeneous tin chloride catalysts exhibited the best performance to form carbon–carbon bonds. The scope and limitations of the synthesis of five‐membered lactones using aldehyde compounds are investigated. The cascade reaction led to high product selectivity as well as diastereoselectivity, and the mechanism leading to the diastereoselectivity was discussed based on isomerization experiments and density functional theory (DFT) calculations. The present results are expected to support new approaches for the efficient utilization of biomass‐derived sugars.     

Reaction of Donor‐Acceptor Cyclobutanes with Indoles: A General Protocol for the Formal Total Synthesis of (±)‐Strychnine and the Total Synthesis of (±)‐Akuammicine

A ligand‐promoted catalytic [4+2] annulation reaction using indole derivatives and donor‐acceptor (D‐A) cyclobutanes is reported, thus providing an efficient and atom‐economical access to versatile cyclohexa‐fused indolines with excellent levels of diastereoselectivity and a broad substrate scope. In the presence of a chiral SaBOX ligand, excellent enantioselectivity was realized with up to 94 % ee. This novel synthetic method is applied as a general protocol for the total synthesis of (±)‐akuammicine and the formal total synthesis of (±)‐strychnine from the same common‐core scaffold.     

One‐Step Multigram‐Scale Biomimetic Synthesis of Psiguadial B

A gram‐scale synthesis of psiguadial B, a purported inhibitor of human hepatoma cell growth, has been achieved in one step by a biomimetic three‐component coupling of caryophyllene, benzaldehyde, and diformylphloroglucinol. This cascade reaction is catalyzed by N,N′‐dimethylethylenediamine, and proceeds at ambient temperature to generate four stereocenters, two rings, one C−O bond, and three C−C bonds. Combined computational and experimental investigations suggest the biosynthesis of the natural product is non‐enzyme mediated, and is the result of a Michael addition between caryophyllene and a reactive ortho‐quinone methide, followed by two sequential intramolecular cationic cyclization events.     

Efficient Synthesis of Cryptophycin‐52 and Novel para‐Alkoxymethyl Unit A Analogues

Cryptophycins are a family of highly cytotoxic, cyclic depsipeptides. They display antitumour activity that is largely maintained for multi‐drug‐resistant tumour cells. Cryptophycins are composed of four building blocks (units A–D) that correspond to the respective amino and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres in a short, efficient and reliable synthesis and contributes to an easier and faster synthesis of cryptophycins. The first two stereogenic centres are introduced by a catalytic asymmetric dihydroxylation, whereas the remaining two stereogenic centres are introduced with substrate control of diastereoselectivity. The stereogenic diol function also serves as the epoxide precursor. The approach was used to synthesise the native unit A building block as well as three para‐alkoxymethyl analogues from which cryptophycin‐52 and three analogous cryptophycins were prepared. Macrocyclisation of the seco‐depsipeptides was based on ring‐closing metathesis.     

Multi‐Gram Scale Synthesis of Chiral 3‐Methyl‐2,5‐trans‐tetrahydrofurans

In this article, we report the rapid and facile synthesis of chiral 3‐methyl‐2,5‐trans‐tetrahydrofurans. This reaction utilizes cheap and easily available starting materials. A domino hydrolysis and intramolecular Michael‐type ring closure reaction was the key step. As a result, synthesis of the desired 3‐methyl‐2,5‐trans‐tetrahydrofurans could be achieved in gram‐scale over seven linear steps with high chemical yield and high diastereoselectivity.     

Bioinspired Total Synthesis of Homodimericin A

Homodimericin A is a remarkable fungal metabolite. This highly oxygenated racemic unsaturated polyketide poses a significant synthetic challenge owing to its sterically demanding central cagelike core containing eight contiguous stereogenic centers (including three quaternary stereocenters) and several carbonyl functionalities. On the basis of its proposed biogenetic synthesis, we designed a total synthesis of homodimericin A that proceeds in seven steps and features a double Michael reaction, an intramolecular Diels–Alder reaction, and an ene reaction.