A Divergent Enantioselective Total Synthesis of Post-Iboga Indole Alkaloids

Divergent enantioselective total syntheses of five naturally occurring post-iboga indole alkaloids, dippinine B and C, 10,11-demethoxychippiine, 3-O-methyl-10,11-demethoxychippiine, and 3-hydroxy-3,4-secocoronaridine, as well as the two analogues 11-demethoxydippinine A and D, are presented for the first time. The enantioenriched aza[3.3.1]-bridged cycle, a common core intermediate to the target molecules, was constructed through an asymmetric phase-transfer-catalyzed Michael/aldol cascade reaction. The challenging azepane ring fused around the indole ring and the [3.3.1]-bridged cycle were installed through an intramolecular S_N2′-type reaction. These cyclization strategies enabled rapid construction of the [6.5.6.6.7]-pentacyclic core at an early stage. Highlights of the late-stage synthetic steps include a Pd-catalyzed Stille coupling and a highly stereoselective catalyst-controlled hydrogenation to incorporate the side chain at C₂₀ with both R and S configurations in the natural products.     

Direct Catalytic Asymmetric Mannich‐Type Reaction of α‐N3 Amide

An α‐N₃ 7‐azaindoline amide serves as a latent enolate to directly engage in an asymmetric Mannich‐type reaction with N‐thiophosphinoyl imines by the action of a cooperative catalyst. The thus‐obtained highly enantioenriched anti‐adduct was transformed into β‐amino‐α‐azido acid in high yield by simple acidic treatment.     

Redox Divergent Synthesis of Fawcettimine‐Type Lycopodium Alkaloids

A new approach for synthesis of fawcettimine‐type Lycopodium alkaloids is described. A divergent strategy was achieved by applying stereoselective Diels–Alder reaction followed by redox‐controlled elaboration. Eventually, (?)‐8‐deoxyserratinine, (+)‐fawcettimine, (?)‐lycopoclavamine‐A, (?)‐serratine, (?)‐lycopoclavamine‐B and (?)‐serratanidine were successfully accessed.     

Total Synthesis of Diaporthichalasin by Using the Intramolecular Diels–Alder Reaction of an α,β‐Unsaturated γ‐Hydroxylactam in Aqueous Media

The first total synthesis of diaporthichalasin has been successfully achieved and complete structure elucidation, including the absolute configuration, was also accomplished. The intramolecular Diels–Alder (IMDA) reaction between the diene side chain on the decalin skeleton and α,β‐unsaturated γ‐hydroxy‐γ‐lactam in aqueous media was effectively employed as the key step. From this synthetic study, we found that α,β‐unsaturated γ‐hydroxy‐γ‐lactam is an essential precursor for the construction of the diaporthichalasin‐type pentacyclic skeleton. This important finding strongly suggests that this route is involved in the biosynthetic pathway for diaporthichalasin.     

Short and Divergent Total Synthesis of (+)‐Machaeriol B, (+)‐Machaeriol D, (+)‐Δ8‐THC,and Analogues

Short and highly efficient stereoselective syntheses provide machaeriols and cannabinoids in a divergent approach starting from a common precursor, commercially available (S)‐perillic acid. Key features of the novel strategy are a stereospecific palladium‐catalyzed decarboxylative arylation and a one‐pot sequence comprising a stereoselective hydroboration followed by oxidation or reduction of the corresponding intermediary boranes. The divergent approach is convincingly demonstrated by the five‐step syntheses of (+)‐machaeriol B, (+)‐machaeriol D, and related analogues, and the four‐step synthesis of (+)‐Δ⁸‐THC and an analogue.     

Formal Synthesis of the Anti‐Angiogenic Polyketide (−)‐Borrelidin under Asymmetric Catalytic Control

Borrelidin ( 1 ) is a polyketide that possesses extremely potent anti‐angiogenesis activity. This paper describes its formal total synthesis by the most efficient route to date. This modular approach takes optimal benefit of asymmetric catalysis and permits the synthesis of analogues; in addition, the high yields and selectivities obtained eliminate the need for separation of stereoisomers. The upper half of borrelidin has been accessed by iterative copper‐catalysed asymmetric conjugate addition of methylmagnesium bromide, whereas synthesis of the lower half of the molecule was achieved by relying on asymmetric hydrogenation and cross‐methathesis as key steps.     

Electrophilic Activation of α,β‐Unsaturated Amides: Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated γ‐Butyrolactones

Although catalytic asymmetric conjugate addition reactions have remarkably advanced over the last two decades, the application of less electrophilic α,β‐unsaturated carboxylic acid derivatives in this useful reaction manifold remains challenging. Herein, we report that α,β‐unsaturated 7‐azaindoline amides act as reactive electrophiles to participate in catalytic diastereo‐ and enantioselective vinylogous conjugate addition of γ‐butyrolactones in the presence of a cooperative catalyst comprising of a soft Lewis acid and a Brønsted base. Reactions mostly reached completion with as little as 1 mol % of catalyst loading to give the desired conjugate adducts in a highly stereoselective manner.     

Asymmetric Total Syntheses of (−)‐α‐Lycorane, (−)‐Zephyranthine,and Formal Synthesis of (+)‐Clivonine

An asymmetric route to (−)‐α‐lycorane and (−)‐zephyranthine, and a formal total synthesis of (+)‐clivonine were achieved. A pivotal intermediate, which serves as a potent precursor for the divergent syntheses of these natural products, was accessed by a diastereoselective Pd‐catalyzed cinnamylation of an N ‐tert ‐butanesulfinyl imine.     

Bioinspired Synthesis of (+)‐Cinchonidine Using Cascade Reactions

The development of efficient syntheses of complex natural products has long been a major challenge in synthetic chemistry. Designing cascade reactions and employing bioinspired transformations are an important and reliable means of achieving this goal. Presented here is a combination of these two strategies, which allow efficient asymmetric synthesis of the cinchona alkaloid (+)‐cinchonidine. The key steps of this synthesis are a controllable, visible‐light‐induced photoredox radical cascade reaction to efficiently access the tetracyclic monoterpenoid indole alkaloid core, as well as a practical biomimetic cascade rearrangement for the indole to quinoline transformation. The use of stereoselective chemical transformations in this work makes it an efficient synthesis of (+)‐cinchonidine.     

Enantioselective Total Synthesis of (+)‐Plumisclerin A

The first and enantioselective total synthesis of (+)‐plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring‐formation protocol was adopted to generate the characteristic tricycle[4.3.1.0^1,5]decane and trans‐fused dihyrdopyran moiety. Scalable enantioselective La^III‐catalyzed Michael reaction, palladium(0)‐catalyzed carbonylation and SmI₂‐mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D‐ring system having six continuous stereogenic centers and two all‐carbon quaternary centers. The trans‐fused dihyrdopyran moiety with an exo side‐chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)‐plumisclerin A.     

Enantioselective Catalytic Aldehyde α‐Alkylation/Semipinacol Rearrangement: Construction of α‐Quaternary‐δ‐Carbonyl Cycloketones and Total Synthesis of (+)‐Cerapicol

An enantioselective aldehyde α‐alkylation/semipinacol rearrangement was achieved through organo‐SOMO catalysis. The catalytically generated enamine radical cation serves as a carbon radical electrophile that can stereoselectively add to the alkene of an allylic alcohol and initiate ensuing ring‐expansion of cyclopropanol or cyclobutanol. This tandem reaction enables the production of a wide range of nonracemic functionalizable α‐quaternary‐δ‐carbonyl cycloketones in high yields and excellent enantioselectivity from simple aldehydes and allylic alcohols. As a key step, the intramolecular reaction was also successfully applied in the asymmetric total synthesis of (+)‐cerapicol.     

Catalytic Michael/Ring‐Closure Reaction of α,β‐Unsaturated Pyrazoleamides with Amidomalonates: Asymmetric Synthesis of (−)‐Paroxetine

A highly enantioselective tandem Michael/ring‐closure reaction of α,β‐unsaturated pyrazoleamides and amidomalonates has been accomplished in the presence of a chiral N,N′‐dioxide–Yb(OTf)₃ complex (Tf: trifluoromethanesulfonyl) to give various substituted chiral glutarimides with high yields and diastereo‐ and enantioselectivities. Moreover, this methodology could be used for gram‐scale manipulation and was successfully applied to the synthesis of (?)‐paroxetine. Further nonlinear and HRMS studies revealed that the real catalytically active species was a monomeric L ‐PMe₂ –Yb³⁺ complex. A plausible transition state was proposed to explain the origin of the asymmetric induction.     

A Concise Total Synthesis of (+)‐Tetrabenazine and (+)‐α‐Dihydrotetrabenazine

Highly concise asymmetric total syntheses of (+)‐tetrabenazine ( 1 ), a drug for the treatment of chorea associated with Huntington’s disease, and of (+)‐α‐dihydrotetrabenazine ( 2 ), an active metabolite of 1 , have been accomplished. Our synthetic route features a trans‐selective enol etherification, followed by an unprecedented cation‐dependent aza‐Claisen rearrangement to establish the carbon framework and two stereogenic centers of tetrabenazine. The syntheses consist of seven steps (34 % overall yield) for (+)‐ 2 and eight steps (22 % overall yield) for (+)‐ 1 .     

Synthesis of (+)‐Discodermolide by Catalytic Stereoselective Borylation Reactions

The marine natural product (+)‐discodermolide was first isolated in 1990 and, to this day, remains a compelling synthesis target. Not only does the compound possess fascinating biological activity, but it also presents an opportunity to test current methods for chemical synthesis and provides an inspiration for new reaction development. A new synthesis of discodermolide employs a previously undisclosed stereoselective catalytic diene hydroboration and also establishes a strategy for the alkylation of chiral enolates. Furthermore, this synthesis of discodermolide provides the first examples of the asymmetric 1,4‐diboration of dienes and borylative diene–aldehyde couplings in complex‐molecule synthesis.     

Total Synthesis of (+)‐Rubriflordilactone A

Two enantioselective total syntheses of the nortriterpenoid natural product rubriflordilactone A are described, which use palladium‐ or cobalt‐catalyzed cyclizations to form the CDE rings, and converge on a late‐stage synthetic intermediate. These key processes are set up through the convergent coupling of a common diyne component with appropriate AB‐ring aldehydes, a strategy that sets the stage for the synthetic exploration of other members of this family of natural products.