Total Synthesis of the Euphorbia Diterpenoid Pepluacetal.

The first total synthesis of the Euphorbia diterpenoid pepluacetal is disclosed in both racemic and chiral fashions. The synthesis strategically relies on a photo-induced Wolff rearrangement/lactonization cascade (WRLC) reaction to access the cyclobutane moiety, a ring-closing metathesis/cyclopropanation sequence to rapidly forge the 7-3 bicyclic system, and a late-stage Rh-catalyzed transannular carbenoid insertion to C(sp3)-H bond followed by a Baeyer-Villiger oxidation and ring-opening manipulations to install the side chain. The synthetic route demonstrates excellent stereochemical control on the non-classical concave-face bond formation, remote traceless stereochemical relay and high scalability to provide 20 mg of (+)-pepluacetal.

Synthesis of the 5-6-7 Tricyclic Core of Daphnicyclidin-Type Alkaloids via a Tiffeneau-Demjanov Ring Enlargement Strategy.

An expedient construction of the 5-6-7 tricyclic core of daphnicyclidin-type alkaloids is described. The synthetically challenging cycloheptanone C ring was constructed via a Tiffeneau-Demjanov ring enlargement reaction from a 5-6-6 tricyclic precursor commonly found in calyciphylline A-type alkaloids. Other key transformations included Davis oxidation, 1,2-addition, oxidation, and dehydration to elaborate the essential cyclcohept-2-enone motif.

Rearrangement of the Tetra- and Tricyclic Skeletons of Pepluanol B to Access the Core Structures of Tigliane- and Myrsinane-Type Euphorbia Diterpenes.

Pepluanol B is a new Euphorbia diterpene with an unprecedented tetracyclic backbone. However, its biogenetic relationship with known Euphorbia diterpenes is unclear. We report herein that its ß-hydroxyl ketone motif could undergo a base-promoted retro-aldol/aldol process in two pathways and afford the skeletons of tigliane- and myrsinane-type Euphorbia diterpenes through the formation of the C8-C14 and C7-C13 bonds, respectively. The retro-aldol/aldol cascade indicates that pepluanol B is possibly a biosynthetic precursor of lathyranes and other relevant dipterpenes.

Total Syntheses of Phleghenrines A and C: A [4 + 2] Cycloaddition and Ring-Expansion Approach.

The first total syntheses of Lycopodium alkaloids phleghenrines A and C have been accomplished in 19 and 18 steps, respectively, relying on three (hetero)-Diels-Alder ([4 + 2]) cycloaddition reactions to forge the cyclic molecular backbone and two ring-expansion reactions to manipulate the ring size. A chiral precursor is synthesized through an auxiliary controlled Diels-Alder reaction, rendering the asymmetric synthesis accessible. The established strategy provides a general approach to the relevant novel Lycopodium alkaloids.

Scalable Total Syntheses of (±)-Catellatolactams A and B.

The first total syntheses of (±)-catellatolactams A and B, two novel ansamacrolactams, are described in 5 and 8 steps, respectively. The strategy relies on an amidation reaction to couple the acylated Meldrum's acid and an aryl amine, a regioselective C-H insertion to construct the γ-lactam moiety, and an RCM reaction to forge the macrocycles with E-olefin. This concise and scalable synthesis provided over 200 mg of the target molecules.

Ten-Step Total Synthesis of (-)-Andranginine.

The total synthesis of the indole alkaloid (-)-andranginine has been achieved in 10 steps. Key reactions of the synthesis include a nucleophilic addition of acetylenyl anion to chiral N-sulfinyl imine, an intramolecular N-alkylation reaction to close the C ring, and a dienyne metathesis cascade reaction to construct the DE rings. Meanwhile, 16-epi-(-)-andranginine was also obtained with the developed strategy.

De Novo Diastereoselective Synthesis of 1-Hydroxyl Allogibberic Methyl Ester en Route to Diverse Bioactive Molecules.

The first de novo synthesis of 1-hydroxyl allogibberic methyl ester, en route to pharbinilic acid and other bioactive molecules, is accomplished in diastereoselective manner. Key reactions of the synthesis include a Pd-catalyzed Suzuki-Miyaura cross-coupling reaction, a Lewis acid-catalyzed reductive Prins cyclization reaction, and a SmI2-mediated transannular pinacol coupling reaction. The synthesis provides a new avenue to access diverse relevant bioactive molecules.

Rapid construction of indole-fused 8-10 membered lactones via a tandem reaction.

An intramolecular anaerobic Mukaiyama hydration-initiated tandem reduction/condensation/acyl migration/aromatization reaction was developed, which enabled the rapid construction of indole-fused 8-10 membered lactones starting from cyclic 2-allyl-2-(2-nitrophenyl)-1,3-diketones. A nitro substituent in the substrates acted as both an oxygen source in the Mukaiyama hydration step and a nitrogen source in a tandem indole ring construction step. Our reaction features mild conditions, atom economy, and inexpensive reagents and it can be conveniently scaled up to a gram scale in modest yields. A rational reaction mechanism was also proposed based on previous reports and control experiments.

Construction of the Skeleton of Lucidumone.

The skeleton of lucidumone was constructed through oxidative dearomatization/intramolecular Diels-Alder reaction, Cu-mediated remote C-H hydroxylation, allyl oxidation, acid-promoted dynamic kinetic resolution cyclization, and benzylic oxidation.

Generation of Fused Seven-Membered Polycyclic Systems via Ring Expansion and Application to the Total Synthesis of Sesquiterpenoids.

Seven-membered polycyclic architectures, widely present in natural products and molecular drugs, are challenging synthetic targets. However, methods for synthesizing fused medium-sized bicyclo[m.n.0] ring systems, including the benzo-cycloheptane systems, are still urgent. Herein we describe a base-induced ring expansion as a general strategy to construct a wide range of fused seven-membered ring systems. The application of this method was demonstrated by the efficient total syntheses of two sesquiterpenoids, plecarpenene and plecarpenone, both bearing a fused bicyclo[5.3.0]decane skeleton.

Collective Total Syntheses of Five Lycopodium Alkaloids.

It is reported herein that by exploiting the commonly shared bicyclic decahydroquinoline motif, a gold-catalyzed enamide-alkyne cycloisomerization reaction is developed to access tricyclic cores in a simple way. These tricyclic cores further serve as an advanced platform for the divergent enantioselective collective total syntheses of five Lycopodium alkaloids, belonging to three different structural types, in a concise and protecting-group-free fashion. The key transformations in the second phase include: 1) a transannular reductive Heck cyclization for installation of the azepane ring in fawcettidine, fawcettimine, and lycoposerramine Q; 2) a domino Mukaiyama hydration/Grob fragmentation process for construction of the ten-membered lactam system in phlegmariurine B; 3) a Fukuyama one-pot protocol for the construction of the 2-pyridone motif in lycoposerramine R. The newly developed strategy is expected to pave the way for the synthesis of other structurally related Lycopodium alkaloids.

Enantioselective α-Functionalization of 1,3-Dithianes by Iridium-Catalyzed Allylic Substitution.

An iridium-catalyzed asymmetric allylic substitution reaction with 2-alkoxy carbonyl-1,3-dithianes has been achieved with high regio- and enantioselectivities. The transformation provides a new method for the enantioselective α-functionalization of dithianes. The corresponding dithiane-containing products are easily converted into many other derivatives with high yields and enantioselectivities.

Total Synthesis of (-)-Gardmultimine A.

The first total synthesis of Gardneria oxindole alkaloid (-)-gardmultimine A has been achieved in 19 steps from d-tryptophan in a fully stereocontrolled manner. This synthesis features (1) an Ir-catalyzed regioselective C-H borylation/oxidation sequence to introduce the C12 methoxyl group, (2) a stereocontrolled oxidative rearrangement of indole to construct the spirooxindole motif, and (3) an Au(I)-catalyzed transannular Conia-ene-type 6-exo-dig cyclization to establish the azabicyclo[2.2.2]octane skeleton and the exocyclic E-alkene with exclusive stereoselectivity.

A Strategy to Construct cis-Hydrocarbazole via Nickel/Lewis Acid Dual-Catalyzed Arylcyanation.

A strategy for the synthesis of cis-hydrocarbazole with a C3 quaternary carbon center has been developed through nickel/Lewis acid dual-catalyzed arylcyanation. A wide array of cis-hydrocarbazoles was accessed with high diastereoselectivities and atom economies in a good yield. The rich chemistry of the installed nitrile group was demonstrated in the preparation of tryptamine- and tryptophol-derived cis-hydrocarbazoles.

Total Synthesis of (-)-Pepluanol†B: Conformational Control of the Eight-Membered-Ring System.

The first total synthesis of the Euphorbia diterpenoid pepluanol B in both racemic and enantioenriched form involves 20 steps from a known bicyclic diol. This synthesis features an unprecedented bromo-epoxidation to control the eight-membered-ring conformation. In addition, salient reactions for the construction of the tetracyclic backbone include a sterically challenging aldol reaction to establish the quaternary center, a ring closing metathesis (RCM) to forge the eight-membered ring, and a diastereoselective cyclopropanation to assemble the embedded cyclopropane motif.

Visible light photoredox catalyzed deprotection of 1,3-oxathiolanes.

An efficient visible light photoredox catalyzed aerobic deprotection of 1,3-oxathiolanes using organic dye Eosin Y as a photocatalyst is disclosed. The deprotection procedure features the use of a metal-free catalyst, mild conditions, a broad range of substrate scope, and good functional group tolerance. 35 examples were tested under the standard conditions and most of them afforded the deprotected products in modest to high yields.

Construction of the Tetracyclic Core of Calyciphylline B-Type Daphniphyllum Alkaloids.

A double cyclization strategy was developed to construct the common tetracyclic core of calyciphylline B-type alkaloids. Key features of the synthesis included asymmetric Evans alkylation, ring-closing metathesis reaction, intermolecular amidation, intramolecular aza-Michael addition, and aldol condensation reactions. This strategy may be applied to the total syntheses of this type of natural product.

Asymmetric Total Synthesis of (+)-Winchinine B.

The first asymmetric total synthesis of aspidosperma alkaloid (+)-winchinine B was achieved in 12 steps from commercially available materials. A new synthetic strategy which features an efficient aza-Michael addition, a ruthenium-catalyzed transfer dehydrogenation, and an intramolecular palladium-catalyzed oxidative coupling was adopted to install the ABC tricycle system. A one-pot process involving carbonyl reduction/iminium formation/intramolecular conjugate addition developed by our group was utilized to construct the D ring moiety.

Total Synthesis of Aspidofractinine Alkaloid Paucidirinine.

The first total synthesis of paucidirinine (1d), a highly congested aspidofractinine alkaloid containing a special contracted five-membered lactam ring, was achieved in 10 steps with 8% overall yield from commercially available materials. Several key maneuvers, including tandem enamination/[4 + 2] cycloaddition reaction and SmI2-promoted radical cyclization, were featured in this potentially scalable strategy.

A rapid construction of the ABC tricyclic skeleton of malabanone A.

The construction of the ABC tricyclic skeleton of malabanone A with the required 4 stereocenters was accomplished in a concise route starting from R-carvone. The synthesis featured an intramolecular [3 + 2] cycloaddition reaction to assemble its A ring and an intramolecular Diels-Alder reaction to construct its C ring.